Research and innovation have been part of the Mayo Aerospace Medicine culture since its inception in the 1930s. Mayo Clinic physiologists and altitude scientists developed several items vital to military pilot safety in the World War II era. Prior to pressurized aircraft cabins for commercial airline passenger flights, aircraft flew at relatively low altitudes to avoid hypoxic (low oxygen) conditions. Mayo scientists developed an oxygen mask for pilots and passengers to wear during flights, allowing travel at higher altitudes above turbulent weather conditions, making flights smoother and more tolerable to travelers.

A variety of other inventions and research developments produced by Mayo Clinic researchers were instrumental in the war effort as well as promoting aviation safety for decades to come.

Today, Mayo physicians and researchers are investigating innovative tools designed to detect and combat spacial disorientation, vestibular abnormalities, and new oxygen delivery systems to be installed in aircraft being developed by major manufacturers. Studies focused on human adaptation at high altitudes and remote locations are also being conducted to mitigate the effects of altitude sickness experienced by individuals visiting destinations at high altitude, and to allow safe air travel at altitudes greater than 40,000 feet (12,100 meters), referred to as "thin air" flights.

With the introduction of a state-of-the-art hyperbaric and altitude chamber facility on the Rochester, Minnesota, campus, and development of a hypoxia simulation and vestibular laboratory at Mayo Clinic's campus in Arizona, Mayo aerospace researchers are advancing various projects applicable to high-altitude aviation as well as programs for space travel.