Raltegravir (RAL) is the first antiretroviral in the integrase strand transfer inhibitors (INSTI) class. The use of RAL has expanded since its approval in October 2007 for multidrug-resistant human immunodeficiency virus type 1 infection in adults. RAL is now a guideline-preferred treatment option for antiretroviral-naïve patients, indicated for treatment in adolescents, and is being studied as an integral part of nucleoside sparing regimens. The development of resistance and the need for a once-daily dosing option has led to the development of new INSTIs, including elvitegravir and dolutegravir. Elvitegravir is being studied in a promising once-daily single-tablet regimen with tenofovir, emtricitabine, and the investigational pharmacoenhancer cobicistat. The development of cobicistat and the new once-daily INSTIs may revolutionize the treatment of human immunodeficiency virus type 1 infection. This article reviews the current literature on raltegravir and new developments in the INSTI class.