Since the introduction of highly active antiretroviral therapy (HAART), the rates of opportunistic infections have decreased markedly as has overall morbidity and mortality from HIV infection in developed countries. However, opportunistic infections remain the most important cause of death in HIV-infected people due to both late presentation of HIV infections and failure of HAART to adequately restore cell-mediated immunity in all individuals. While prophylaxis may be discontinued in patients who have responded to HAART with sustained increases of their CD4 counts above risk thresholds, for those patients who fail HAART, those who are unable to tolerate it, or whose treatments are interrupted, opportunistic-infection prophylaxis remains essential. Some HIV-associated diseases, such as anogenital human papilloma virus-induced neoplasia and hepatitis C infection, have not decreased in frequency with the advent of HAART. For these conditions, effective screening and treatment programs will be necessary to prevent ongoing morbidity. This review will provide an update on HIV-associated opportunistic infections and their prevention in the age of HAART, as well as discuss novel presentations of opportunistic illnesses, such as immune restoration syndromes.