In 1935, EMC built a total of five locomotives to test the use of large mainline diesel locomotives under everyday conditions. These were two company demonstrators, one for the Baltimore & Ohio and a double set for the Santa Fé. Since there was no production capacity for large diesel locomotives at that time, they turned to General Electric and the St. Louis Car Company.

The basic idea was to install two diesel engines, each with its own generator and about 50 percent more total power, instead of just one diesel engine. Since the engines were less heavily loaded on average, less wear and tear and a longer service life could be expected. If one engine or generator failed, the locomotive could continue to run with the other. The concept of having a driver's cab at each end was new, but was not pursued on later American diesels.

For cost reasons, the two demonstrators had got simple, box-shaped bodies like earlier boxcabs. For the first time, they were given multiple controls, so that both locomotives could be controlled by one engineer at the same time. In fact, they were often used together to achieve the same power as one large steam locomotive. After extensive trials, they were scrapped in 1938.

The Baltimore & Ohio received a locomotive identical to the first two and that was numbered 50. It soon got a slanted fairing on one end, also known as a “Shovel Nose”. This was removed again during World War II. In this form, the locomotive was still used for local freight and passenger trains for a while after the end of the war. It later ended up in the National Museum of Transportation in St. Louis, Missouri and can still be found there today.

The double locomotive of the Santa Fé was managed as one complete unit and received the number 1. It had streamlined shapes, covered bogies and an attractive color scheme. The company's network had long stretches that led through deserts and mountains and offered good conditions for testing the new technology. Their advantage over steam locomotives was that they were not dependent on water supplies and could cover long distances with one tank of diesel.

The 2,226.6-mile route, which was regularly run with passenger trains, served as preparation for the later operation of the streamlined trains and revealed a few teething problems. The fairing on the bogies soon had to be removed due to repeated overheating problems. The hood over the air intakes above the driver's cabs also impeded cooling, so that additional air intakes on the roof were necessary. The locomotive was later reinforced with one of the EMC demonstrators. In 1938, one cab was removed and a “Bulldog Nose” formed, as was also found on the later production locomotives. In addition, both bogies each received a leading axle. The locos were returned to EMD in 1953 and rebuilt to booster units.

The locomotives provided many insights which were implemented in the series production of the E series. These were powered by the same Winton engines, initially each with 900 hp, but had bogies with a central carrying axle. The multiple control was soon adopted by all manufacturers and is still used today in almost all North American diesel locomotives in a form that has hardly changed.

With the first generation of E-units, EMC made on step away from the custom-built diesel streamliners towards standardized, mass-produced passenger locomotives. As EMC's new owner GM was convinced that styling was more important than technical advances, they put much effort into the streamlined nose. Technically, they still had many similarities to the earlier, integrated power units of the famous streamliner trains. The designation “E” came from “eighteen hundred”, what was the total number of horsepower per unit.

Power still came from the proven Winton 201-A two-stroke engines. Each unit had two 900 hp engines, which had one generator each and powered two three-axle bogies with an A1A arrangement. Each locomotive was either an A-unit with a cab at one end or a B-unit with no cab at all. Usually, two or three units were coupled together and operated by a single crew to haul a heavy passenger train. In total these had 3,600 or 5,400 hp, what was the typical power range of the big steam passenger locomotives of the time.

In 1937 and 1938, three models were built for three customers which were identical for the most part. The Baltimore & Ohio received six EA and six EB. The E1 was developed for the ATSF, which received eight A-units and only three B-units. These were rebuilt to E8 in 1952 and 1953. For the famous trains “City of San Francisco” and “City of Los Angeles”, two A-units and four B-units of the E2 were jointly owned by the Union Pacific, Chicago & North Western and the Southern Pacific. Five of these were also later rebuilt to E7 or E8. These optically differed from the EA and E1 by having the bulldog nose also seen on later EMD locomotives.

The EMD F-series designated several types of four-axle diesel-electric freight locomotives of which more than 7,500 were built between 1939 and 1960. They came after the A1A-A1A E-series passenger locomotives, where the E stood for “eighteen hundred”, designating the total installed horsepower. With the 16-cylinder variant of the 567-series engine initially delivering 1,350 hp, the new locomotive series got the letter F for “fourteen hundred”.

As the initial model was usually marketed as a twin set consisting of an “A” cab unit and a “B” booster unit, it was called FT with the T for “Twin”. The first locomotives built for a customer were delivered to the ATSF in December 1940. They were the first diesel-electric locomotives equipped with a dynamic brake since the customer insisted on that. The FT was not only used as A-B set, but also as a A-B-B-A set delivering 5,400 hp or even as an A-B-A set.

The FT is mostly been seen as the locomotive that proved that diesel traction was the future of freight service. Since the War Production Board limited the construction of diesel locomotives for civil usage, EMD was lucky since they did not produce steam locomotives as an alternative. So they could quickly win the market lead and establish the widest customer base for the time after the war when other manufacturers could resume production of diesel locomotives without restrictions. When production of the FT ended in November 1945, 555 A units and 541 B units had been completed.

The next variant was the F2 that did not have many differences compared to the FT. Only 74 A units and 30 B units were built. The biggest numbers were produced of the F3 and F7 which had the “B” variant of the 567 engine that delivered 1,500 hp. Of the F3, 1,106 A units and 694 B units were built between 1945 and 1949. The F7 even reached higher numbers with 2,393 A units and 1,463 B units between 1949 and 1953. Additionally, 381 of the FP7 were built, what was a dedicated passenger variant that was four feet longer due to its steam heating boiler.

The last iteration of the F series was the F9 that produced 1,750 hp with the 567C engine. Although production ran until 1960, only 101 A units and 156 B units could be sold. This can be explained with the fact that the road switchers of the GP series already established themselves since the beginning of the fifties. There was also an FP9, but only 90 of this could be sold.

In 1935 EMC manufactured a total of three prototypes of a heavy switcher, which were equipped with the Winton engine, of which the E-series had two. Two of these switchers had a 600 hp in-line 8-cylinder engine, while the third had a 900 hp V12. All had the same frame length, but with the more powerful version, the body was longer. A special feature of the hoods over the machinery was that the ceiling tapered to the driver's cab to improve visibility.

The production locomotives received an S for “six hundred” in the version with 600 hp, while the version with 900 hp received an N for “nine hundred”. There were also two different types of frames, which can be distinguished by the second letter in the type designation. The first version was cast by General Steel Castings and therefore has a C for “cast”, while the other was welded by EMC themselves and therefore has a W for “welded”.

The SC, SW, NC and NW types initially resulted from the combinations of engine and frame. Other versions of the more powerful variant were built, which differed mainly in terms of the electrics and were designated NC1, NC2, NW1 and NW1A. Two more copies were made from the NW4, which were lengthened and had an additional steam generator. These were used by the Missouri Pacific for switching passenger cars. A total of 175 series locomotives were produced up to 1939.

A single one was only given the type designation T and basically consisted of two power trains from the N series, which stood on four two-axle bogies with a driver's cab in the middle. With an output of 1,800 hp, it was intended to transfer freight trains between nearby marshalling yards and was not built in series because the long frame settled over time.

Since the gas turbine locomotives built for the Union Pacific in the 1950s did not manage to establish themselves as standard locomotives for very heavy trains, the development of particularly powerful diesel locomotives was tackled again in the 1960s. However, the power of the individual prime movers was limited, so it was decided to combine the power plants of two locomotives each on a common frame. Thus, there were two 16-cylinder series 567A, each with its own generator, on a frame, which in turn stood on two four-axle bogies. 

The first model was the DD35, which was built 30 times in 1963 and 1964, mainly for the Union Pacific. Their power plants were identical to those of a GP35, giving a combined output of 5,000 hp. They did not have a driver's cab and were intended for use as a B unit together with classic diesel locomotives. Since the four-axle bogies at the front of the train greatly reduced the service life of the rails, no A-units with a driver's cab were initially built. It was mostly used with two DD35s between two GP35s, giving a total output of 15,000 hp. It was not until 1965 that 15 DD35A cab-units followed, built exclusively for the Union Pacific. Both types had in common that the sandboxes were initially in the engine room and sand flying around caused problems in the electrical system there, which led to the sandboxes being relocated to the circulations.

The high point of the development of the eight-axle EMD locomotives were the DDA40X “Centennial”, of which 47 units were built between 1969 and 1971 for the Union Pacific. New 16-cylinder series 645 prime movers were now used, which brought the total output to 6,600 hp. Thanks to further developments on the bogies, it was no longer a problem if such a locomotive led the train. Inside, many new assemblies were used, which later came into other EMD locomotives. The driver's cab was of the wide design used on the FP45.

In day-to-day operation, however, it soon became apparent that such a powerful locomotive hardly brought any operational advantages compared to two smaller ones and was less flexible to use. For this reason, no further eight-axle large diesel locomotives were later developed, apart from special narrow-gauge machines with low axle loads. All later models had only four or six axles and were or are mostly used at least double-headed. Even today, when the current standard diesel locomotives have an output of more than 4,000 hp, trains with ten locomotives are formed on mountain routes. Also the already built DD35s and DD35As were phased out in the early 1980s and the DDA40Xs in the middle of the decade.

Milwaukee Road ordered 15 six-axle passenger locos in the early 1970's for service on commuter rail routes around Chicago, which were designated F40Cs. EMD used the SDP40F as a base, but replaced the steam boilers with an additional diesel generator for use with new electrically heated passenger cars. The 16-cylinder used here delivered 3,200 hp. Since other railway companies no longer needed six-axle passenger locomotives, the 15 units remained. When Metra was founded in 1984 for passenger transport in the Chicago area, the locomotives became their property. In the years after the turn of the millennium they were replaced by MP36PH.

Since Amtrak only wanted to procure four-axle passenger locomotives in the future and, due to inadequacies in the steam-powered train heating systems, procured a large number of cars with electric heating, the four-axle F40PH was delivered from 1975. The prime mover delivered 3,000 hp and at the same time drove a second generator, which, depending on the series, generated up to 500 or 800 kW to supply the cars. In order for this generator to generate three-phase current at the required frequency, it was necessary for the engine to run constantly at a nominal speed of 893 revolutions per minute. This made them one of the locomotives that made a loud engine noise even when stationary. Later series received an additional diesel generator and some existing locomotives were retrofitted with it so that they could run at low speeds when idling and more power was available for the traction motors. Retrofit machines are designated F40PH-2C or F40PH-CAT depending on whether the alternators are powered by Cummins or Caterpillar engines.

Of the 475 F40PHs built by EMD, Amtrak had received 210 by 1988. 132 of these were created by Amtrak returning the unpopular SDP40F to EMD and using their engines to build an F40PHR. Other important customers included the Illinois Regional Transportation Authority and Canada's Via Rail. Some vehicles had a slanted front instead of the classic hood. Another 31 pieces were made between 1988 and 1998 by Morrison-Knudsen and MotivePower Industries. Many F40PH were also replaced by the MP36PH after the turn of the millennium, but others continued to be used after 2010. Some machines entered freight service and were fitted with a shorter gear ratio for 65 mph.