The global impact of the HIV epidemic on the prevention and management of tuberculosis has resulted in added levels of complexity for physicians and other health- care workers caring for these patients. In addition to the usual difficulties associated with drug toxicities and regimen adherence, the concomitant treatment of HIV and tuberculosis is complicated by drug interactions between antiretroviral agents and the antituberculous containing rifampin-based regimens, and the frequent occurrence of the tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). Currently, the best antitubercular regimens include a rifamycin, usually rifampin, because of the high cost of rifabutin. Two nucleosides combined with efavirenz is the best antiretroviral alternative for patients who are receiving rifampin. Issues regarding the duration of anti-tubercular therapy before starting antiretroviral therapy (ART) need further clarification. The standard recommendation of waiting 8 weeks before starting ART is accompanied by significant morbidity and mortality, and has recently been challenged by data suggesting that 2 weeks is adequate. Ongoing studies looking at concomitant anti-inflammatory therapies for prevention of TB-IRIS may allow initiation of therapy for both diseases nearly simultaneously. The increase rates of M(X)DR tuberculosis isolates is not only testimony to the technical inability of the currently available tools for diagnosis and treatment of resistant TB but also the massive structural, social, political and economical constraints that most affected countries face. There is a critical need for novel antituberculous agents, but before they are made freely available, widespread investments in tuberculosis control programs are needed in order to ensure the application of practical and cost-effective community-based directly observed therapy and thus to protect these novel agents from the same fate as the current first line agents.