Approximately 10% of emphysema patients have rarely or never smoked tobacco. Emphysema in the nonsmoking population has been recognized in a variety of processes. These include ␣-1-antitrypsin deficiency, nutritional deficiency, human immunodeficiency virus (HIV) infection, illicit drug use (both intravenous and inhaled), occupational and environmental exposures such as coal dust, silica and cadmium and connective tissue disorders, including Marfan syndrome and Ehlers-Danlos syndrome. In this review, we discuss these causes of emphysematous changes in the lungs through an evaluation of the existing literature. We focus specifically on the evidence behind proposed causal links and the hypothesized pathogenesis of emphysema in each category. Implicated mechanisms for the development of emphysema in these patients include alterations in lung tissue development and repair, oxidant stress, aberrant release of white blood cell mediators, and endotoxin induced damage.(Clin Pulm Med 2008;15: 1-7)