The Reichsluftfahrtministerium (RLM), the Reich Aviation Ministry, first learned of the American Boeing B-29 Superfortress heavy bomber in late 1942.

Serious concerns as to B-29 capability developed in early 1944, when YB-29 "Hobo Queen" made a well-publicised appearance at RAF Bovingdon, which had been cryptically hinted at in an American-published Sternenbanner German language propaganda leaflet from Leap Year Day in 1944, meant to be circulated within the Reich.

To counter the B-29, the Luftwaffe would need new day fighters and bomber destroyers with greatly enhanced performance at extreme altitude.

The fighter chosen was the Focke-Wulf Ta 152H, a derivative of the Fw 190D with a longer wingspan and powered by the new high-altitude model "E" of the Junkers Jumo 213 engine.

An alternative fighter model was the Messerschmitt Me 155B, a long-winged development of the Bf 109, which had already undergone several stages of design and would ultimately be built in prototype form by Blohm & Voss.

The centre-line thrust, twin-engined Dornier Do 335, powered with two of the competing Daimler-Benz DB 603 engines also offered a service ceiling of some 11,400 m (37,500 ft), but the promising Dornier heavy fighter and zerstörer was still under development with only prototype airframes flying, and the first production examples expected to enter operational service late in 1944.

For the bomber destroyer and night fighter roles, the all-wood Focke-Wulf Ta 154 and metal-structured Heinkel He 219 had the performance needed to catch the bomber; however, both designs only gained that performance by mounting low aspect ratio wings which were inadequate for flight at high altitude and resultingly produced too high a wing loading.

German photo-reconnaissance efforts had practically disappeared due to the increased performance of the Allied defenses, so production mostly concentrated on the L model.

In August 1944, Japanese Major-General Osamu Otani, a member of one of the commissions related to the Tripartite Pact and serving in Berlin, expressed interest in a license production of the Ju 388.

[3][page needed] Complete drawing sets for the Ju 388 were handed over to the Japanese as well as the rights for licensed production.

The Ju 388L-1 reconnaissance version with construction number (Werknummer) 560049 was the eighth of the series manufactured at Weser Flugzeugbau's Nordenham plant.

The Ju 388 was flown for 10 hours of flight tests at Wright Field near Dayton, Ohio with the "foreign evaluation" serial number FE-4010 (later changed to T2-4010).

The Ju 388 was donated to the Smithsonian Institution's National Air Museum on 3 January 1949 and arrived at Silver Hill, Maryland, for storage in November 1954.