Therapy recommended for preventing and treating drug-resistant tuberculosis is discussed. Drug-resistant strains of Mycobacterium tuberculosis can be transmitted by an infected individual, or resistance can be acquired during therapy for drug-susceptible disease. At least until susceptibility test data are available, the recommended initial treatment for tuberculosis consists of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Resistance has led to variations on this regimen that sometimes include more toxic alternative drugs, including ethionamide, aminosalicylic acid, cycloserine, and capreomycin, as well as ciprofloxacin and ofloxacin. Drug regimens used for retreatment usually include the alternative drugs. Success in treating drug-resistant tuberculosis varies. Therapy to prevent resistant tuberculosis is recommended for any individual with a positive skin-test result and any of the following: infection with the human immunodeficiency virus (HIV), close contact with a newly diagnosed patient, recent conversion to a positive skin-test result, or a predisposing medical condition. Although isoniazid is the only drug with FDA-approved labeling for use as prophylaxis in patients with latent tuberculosis, the Centers for Disease Control and Prevention suggests several two-drug combinations. Fluoroquinolones are recommended for both treatment and prevention. Patient compliance and HIV infection are special issues in managing resistant tuberculosis. Drug-resistant tuberculosis is a growing problem that must be addressed through appropriate prophylactic and treatment measures.