Opportunistic infections (OIs) are the hallmark of the immunodeficiency associated with HIV infection. Prophylaxis strategies have improved the morbidity and mortality associated with AIDS. The widespread use of highly active antiretroviral therapy (HAART) has brought about a change in the natural history and clinical manifestations of OIs; a decline in the incidence of most OIs; and an improvement in the clinical outcome of many OIs. The possibility of immune reconstitution raises questions about whether withdrawal or prophylaxis is safe and, in some cases, whether certain diseases may be curable without lifelong maintenance prophylaxis. Ongoing studies should provide information about the safety of removing primary and secondary prophylaxis in patients who respond to HAART. This review will update clinicians on the current state of the art of prophylaxis and treatment of OIs in patients taking HAART.