The frequency of infections with M. tuberculosis resistant to antituberculous drugs is increasing in the United States and globally. This increase is a major threat to tuberculosis treatment and control programs. To prevent this situation from worsening, initial treatment programs that entail directly observed therapy supported by effective inducements or enforcements must be used. Retreatment of patients who have multidrug-resistant tuberculosis should be carried out in programs with comprehensive microbiologic, pharmacokinetic, psychosocial, and nutritional support systems. Regimens of multiple drugs, which generally are poorly tolerated and more toxic than traditional regimens, must be administered for 18 to 36 months. Resectional surgery may be required for substantial numbers of patients. For patients with AIDS who acquire tuberculosis caused by multiply-resistant strains, the disease may prove lethal before effective therapy can be implemented. Ultraviolet irradiation systems should be used to protect health care personnel and other patients in high-risk environments. Enhanced federal, state, and local programs for prevention and control are urgently needed, and research to identify new medications and systems for their delivery is essential.