The prevalence of tuberculosis in the homeless is on the rise. The presence of human immunodeficiency virus and multidrug-resistant tuberculosis in the homeless has contributed to this high prevalence. Several factors, including alcoholism, substance abuse, and psychiatric illness, combine to make it difficult to diagnose and treat tuberculosis in the homeless. Medical providers are likely to encounter homeless individuals in a number of settings, including emergency departments, community and free clinics, public hospitals, and health maintenance organizations. Appropriate screening, prevention, and treatment should be undertaken in collaboration with local health departments. The use of directly observed therapy and of the treatment regimens published by the Centers for Disease Control and Prevention improves treatment outcomes among the homeless.