Characterization of the mechanisms by which HIV-1 enters cells has allowed for an increased understanding of not only tropism and pathogenesis, but also the identification of new targets for rational drug design. Several classes of HIV-1 entry inhibitors have been developed. Antagonists targeting the interaction of the viral envelope protein and receptors on the cell surface, as well as peptides that target an intermediate in the fusion process, have shown promise in vitro and are currently being evaluated in clinical trials. The addition of entry inhibitors to current drug regimens has the potential to significantly improve the therapeutic options for infected individuals, which is crucial for those resistant to or failing currently available therapies.