The major airframe application of the Wright R-3350 was the Boeing B-29 during World War II. Rushed into service, the engine had many difficulties, initially resulting in many losses from engine fires on takeoff. Typified by this version used in later B 29s such as the Enola Gay, also displayed at the museum, the problem was eventually solved with improvements including replacement of the carburetors with fuel injectors.

The engine was also used on the Martin PB2M Mars flying boat, and other models continued to serve in commercial aviation long after the war. One version was the first of its type to have its exhaust turbines (three of them) geared into the power system. Called the Wright Turbo-Compound Cyclone, it was the last and the most highly developed piston engine to be widely used in large military and commercial airplanes, including the Douglas DC-7 and Lockheed Super Constellation.