The emergence of antiretroviral drug resistance in patients infected by the human immunodeficiency virus (HIV) has prompted efforts to develop new antiretrovirals that differ from existing agents with regard to mechanism of action and resistance profiles. We evaluated the literature regarding a new class of antiretrovirals, the integrase inhibitors. A MEDLINE search (January 1996-May 2007) was performed to identify relevant clinical trials and review articles; abstracts from HIV conferences were also searched. Raltegravir (MK-0518) and elvitegravir (GS-9137) are the two integrase inhibitors in late-phase development. These agents prevent viral DNA integration into the CD4(+) cell chromosome. Both drugs showed potent antiviral activity in large clinical trials that were performed in treatment-experienced, multidrug-resistant patients. Promising results have also been seen in an initial dose-ranging study with raltegravir in treatment-naïve patients. Preliminary data describe integrase inhibitor resistance profiles, but more data are needed in this area. Both agents were well tolerated in clinical trials, with favorable pharmaco-kinetic profiles for once- or twice-daily dosing. Raltegravir and elvitegravir differ in their metabolism, resulting in distinct drug-interaction profiles for each agent. Based on available data, this new class of antiretrovirals will soon be widely used in antiretroviral-experienced patients infected with HIV. In the future, this class of drugs may become a reasonable treatment option for antiretroviral-naïve patients, but more data are needed in that patient population.