The institution of highly active antiretroviral therapy (HAART) in HIV-infected patients restores protective immune responses against a wide variety of pathogens and dramatically decreases mortality. In a subset of patients receiving HAART, immune reconstitution is associated with a pathological inflammatory response leading to substantial short-term morbidity and even mortality. The past several years have seen marked advances in our clinical understanding of the immune reconstitution inflammatory syndrome (IRIS), but many questions remain. This article summarizes recent data on clinical risk factors for the development of IRIS. A consistent finding from multiple groups is that IRIS develops in a substantial percentage of HIV-infected patients who have an underlying opportunistic infection and receive HAART. As the use of HAART stands to markedly increase over the next several years, optimal care of patients receiving HAART will need to incorporate monitoring for and treating complications of IRIS.