Chemotherapy for tuberculosis in general and osteoarticular tuberculosis in particular poses certain peculiar problems that include chronicity of infection, infection by resistant mycobacteria, persistent mycobacteria, possibility of concomitant human immunodeficiency virus infection, and drug toxicity during prolonged treatment. Although the success rate of chemotherapy is greater than 90% with optimum drug combination regimens currently used, there is a need for additional improvement. A successful outcome depends on using an optimum regimen, which contains safer and more effective drugs given regularly for an adequate period. The most important cause of treatment failure is poor patient compliance, which can be improved by using supervised drug treatment programs. In a few patients, surgical removal of infected tissue may be indicated to improve the efficacy of chemotherapy. In the future, safer and more effective antimycobacterial and antiacquired immunodeficiency syndrome drugs may become available. Research in various related fields also is expected to additionally improve prophylaxis and treatment.