The national and international emergence of drug-resistant M. tuberculosis has complicated both the programmatic control of the tuberculosis epidemic and the clinical management of individual cases. In the United States, the problem of MDR tuberculosis is regionalized and likely stems from multifactorial causes, including the concurrent HIV epidemic. The epidemic is propagated by two distinct entities, PDR and ADR tuberculosis, which result from different inadequacies in tuberculosis control programs. The clinical management of drug-resistant tuberculosis, MDR tuberculosis in particular, is complex, frequently results in adverse outcomes, and often necessitates consultation with a specialist in the field. Two important management principles are to always use at least two agents to which the organism is susceptible and to never add a single drug to a failing regimen. Selection of an appropriate treatment regimen and determination of the duration of therapy depend on the resistance pattern, toxicities of the drugs, and the patient's response to therapy. Measures to ensure patient adherence with therapy are of paramount importance in the setting of drug resistance. Preventive therapy should be considered in the management of close contacts to active cases of MDR tuberculosis, although there is little evidence to support this practice.