The Cape Girardeau Regional Airport began in 1942. It was then called Harris Field and was used as a training grounds for Air Force pilots. In 1945, the school closed and the airport reverted to the War Assets Administration as surplus property. In 1946-1947, the City of Cape Girardeau acquired the airport and it became known as Cape Girardeau Municipal Airport. The Consolidated School of Aviation moved their operations to Cape Girardeau Municipal Airport at this time. The school had been operating at the site of R.B. Potashnick Construction Company.

There was only one runway at the time the City of Cape purchased the airport. It was runway 02-20, which was half asphalt and half sod. The runway was 4000 feet long (about 13.5 football fields laid end to end) and was aligned northeast by southwest. 1948, the first expansion of the airport began with asphalt being placed on the south half of runway 02-20, the construction of sod runway 12-30, runway lights and center taxiway lights. In 1950, Ozark Airlines became the first scheduled airline to come to Cape and was only certified for Visual Flight Rules (VFR) operations. The Consolidated School of Aviation sold their assets and Cape Central Airways was formed. A terminal building was built where the present fuel farm is located. The terminal consisted of offices for Cape Central Airways and Ozark Airlines, classrooms, a restaurant, and an apartment for the restaurant manager.

In 1956, the terminal building caught fire and the building was destroyed. Cape Central Airways and Ozark Airlines moved their operations to an existing hangar. In the late summer of 1956, the north end of runway 02-20 was destroyed due to flooding and ground saturation.

In 1956-1957, the north end of runway 02-20 was reconstructed as a concrete runway, the first section of the existing terminal, a ramp with a taxiway, a taxiway leading to the approach end of runway 20, and a parallel taxiway from the center taxiway to the approach end of runway 02. In 1960, a Flight Service Station (FSS) was located at the airport and improved taxiway and runway lighting was installed.

In 1963, four wooden hangars were built. Cape Central Airways used one of the four for a maintenance facility, a naval reserve unit occupied one, and the other two were used for storage. In 1966, one of the storage buildings burned down after being struck by lightning. In 1967, the VOR was constructed and VOR approaches were established. In 1968, runway 10-28 was constructed with high intensity lights and taxiways. The terminal building was also expanded and a restaurant included. In 1971, Cape Central Airway maintenance facility was destroyed by lightning and their present building was built. In 1973-74, construction of the air traffic control tower began.
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