The advent of highly active antiretroviral therapy (HAART) has revolutionised the management of HIV. A wide selection of antiretroviral agents with various mechanisms of action is now available, allowing patients and physicians a greater choice of effective therapy. This article details the development of the HIV entry inhibitors, describing the physiology and pharmacology involved in their design, and their use in individuals at all stages of HIV infection. We focus on the CCR5 antagonists, a novel class of HIV entry inhibitor and detail the findings of the recent MERIT and MOTIVATE trials, designed to investigate CCR5 antagonist use in the antiretroviral naive and highly treatment experienced populations, respectively. Drug resistance and toxicities have emerged as major treatment challenges in the HAART era and the development of novel antiretroviral agents remains paramount. This article discusses how the entry inhibitors may meet many of these challenges and preserve the reduced morbidity and mortality we have come to expect from HAART use.