The present study was performed to clarify the effects of papain on rat lung connective tissue by electron microscopy. Preliminary studies were performed with rat aortas incubated in vitro with papain to establish histologic criteria for papain-induced elastolysis. Rats were exposed to an aerosol of 10 per cent papain for 4 hours, and their lungs were examined at intervals from immediately to 6 months after exposure. Papain selectively attacked the amorphous component of elastic fibers, leaving the microfibrils intact. Collagen was not altered histologically. Connective tissues appeared normal in animals examined later than 4 weeks after exposure. A pathogenetic mechanism for the development of emphysema is proposed that involves the acute dissolution of elastin by proteolytic enzymes, allowing structural remodeling of the lung, with subsequent regeneration on the persisting microfibrillar skeleton. This concept would unify morphologic observations with the biochemical observations that connective tissues are not altered in emphysema.