The pulmonary blood-gas barrier is an extraordinary structure because of its extreme thinness, immense strength, and enormous area. The essential components of the barrier were determined early in evolution and have been highly conserved. For example, the barriers of the African, Australian, and South American lungfish that date from as much as 400 million years ago have essentially the same structure as in the modern mammal or bird. In the evolution of vertebrates from bony fishes through amphibia, reptiles, and ultimately mammals and birds, changes in the pulmonary circulation occurred to limit the stresses in the blood-gas barrier. Only in mammals and birds is there a complete separation of the pulmonary and systemic circulations, which is essential to protect the extremely thin barrier from the necessary high-vascular pressures. To provide the blood-gas barrier with its required strength, evolution has exploited the high ultimate tensile strength of type IV collagen in basement membrane. Nevertheless, stress failure of the barrier occurs under physiological conditions in galloping Thoroughbred racehorses and also apparently in elite human athletes at maximal exercise. The human blood-gas barrier maintains its integrity during all but the most extreme physiological conditions. However, many pathological conditions cause stress failure. The structure of the blood-gas barrier is apparently continually regulated in response to wall stress, and this regulation is essential to maintain the extreme thinness but adequate strength. The mechanisms of this regulation remain to be elucidated and constitute one of the fundamental problems in lung biology.