The advent of highly active antiretroviral therapy (HAART) has revolutionized the treatment of HIV. A wide variety of antiretroviral agents are now available, allowing patients and physicians a choice of effective therapy. However, drug resistance and toxicities are emerging as major treatment challenges in the HAART era. The development of agents within existing and novel antiretroviral classes remains paramount in order to preserve the reduced morbidity and mortality we have come to expect from HAART use. This article details the development of the HIV epidemic, reviewing current and future treatment strategies, and concentrating upon the viral entry inhibitors.