When confronted with a case of multiple drug-resistant tuberculosis (MDR-TB), we face an important therapeutic challenge as a result of the loss of efficacy to the key antimycobacterial agents: isoniazid and rifampin. The situation is often compounded by the presence of severe clinical forms, multiple organ involvement, and comorbidities. The treatment scheme should be based on the sensitivity of the organisms. A thorough understanding of the safety, tolerability, and efficacy of alternative agents will be required. Alternative schemes should always be considered of reduced efficacy when compared with the standard of isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin. Alternative therapeutic schemes, not containing isoniazid and rifampin, will be associated with a slower rate of bacteriologic cure and a higher frequency of relapses. It is therefore important that these patients be monitored closely and for at least 18 months after cultures have become consistently negative. In this article, we describe the therapeutic agents available for the management of MDR-TB. We also provide some rules of how to optimize their use, on the basis of our experience in dealing with a large nosocomial outbreak that recently involved a major teaching hospital in Argentina.