Human immunodeficiency virus (HIV) infection affects close to 40 million individuals worldwide. Since 1981 when the first case reports of individuals dying from a then rare opportunistic infection were published, twenty million people have died from this epidemic. With 3 or more antiretrovirals as the standard of care, the prevalence of single, double and triple-class resistant HIV strains has increased significantly over the last 5 years due to the tremendous replicative capacity of HIV and selective drug pressure. With greater resistance comes the need for novel and effective antiretrovirals to treat these resistant strains. The purpose of this review is to highlight the most promising agents and classes in Phase II-III drug development by assessing the clinical efficacy, pharmacology, resistance and tolerability. Three out of the four existing antiretroviral classes (nucleosides, non-nucleosides, protease inhibitors) with agents in clinical trials will be discussed such as nucleoside reverse transcriptase inhibitors (D-d4FC, SPD754), non-nucleoside reverse transcriptase inhibitors (capravirine, TMC125) and protease inhibitors (tipranavir, TMC114). In the next several years, antiretrovirals from novel pharmacologic classes will enter the HIV armamentarium. Based on the early clinical studies, these promising agents will be reviewed from the following classes: attachment inhibitors (TNX-355, BMS-488043), CCR5 coreceptor antagonists (SCH-D, UK-427857, GW 873140) and a maturation inhibitor (PA-457). It is hoped that these agents will represent a therapeutic advance and better activity against HIV resistant strains by providing effective therapy that will reduce viral load, increase the CD4+ cell count and ultimately, prolong survival with minimal adverse effects.