The diagnosis of diffuse pulmonary emphysema is being made more frequently throughout the world. The cause of this disease remains uncertain. It is probably a late manifestation of various pathogenetic origins. A tissue defect, congenital, developmental, or acquired, appears to play a fundamental role; an acquired tissue defect may well arise from environmental sources, some of which may be industrial or occupational. Chronic and recurrent infections and chronic irritation from smoking or coughing, or both, appear to play important supplementary, if not primary roles. These opinions are based upon clinical, physiologic, and morphologic studies of a series of 123 human subjects with emphysema, upon surveys of 2 small working populations searching for symptoms and objective evidence of emphysema, and upon a review of the literature.