From February 1984, through March 1985, a total of 26 cases of tuberculosis (TB) were verified in homeless persons in Boston. Fifteen cases were resistant to isoniazid (INH) and streptomycin (SM) and were most likely the result of a common source exposure to one or possibly two highly infectious persons. Five cases without multiple drug resistant organisms occurred in persons with previous positive tuberculin tests who had not received adequate therapy for prophylaxis of infection or treatment of disease. The remaining cases were in persons with a previous negative skin test or no history of ever receiving a skin test. A screening program using chest roentgenograms (CXR), skin tests, and sputum smears led to the identification of several cases. CXR, the most readily accepted test, was the mechanism by which all cases detected through screening were identified. Detection and therapy of TB in the homeless, a group at particular risk for disease, required intensive intervention and outreach efforts.