PURPOSE OF REVIEW: To provide an update on viral entry inhibitors focusing on recently published clinical trials, the routine clinical use of these medications, and future drug candidates. RECENT FINDINGS: Clinical trials and cohort studies support the efficacy of both enfuvirtide and maraviroc in the management of treatment-experienced patients. In clinical practice, tolerability issues, particularly injection site reactions, have limited the clinical use of enfuvirtide. Providers should be aware of the need for tropism determination and dosing requirements for maraviroc. The novel chemokine (C-C motif) receptor 5-blocking agent, vicriviroc, has shown promise and is currently in phase III clinical development. SUMMARY: The rapid pace of scientific discovery and pharmaceutical development has led to the release of several novel and well tolerated antiretroviral agents, with activity against resistant isolates. Entry inhibitors remain a critical therapeutic option for treatment-experienced patients. Providers need to be familiar with these agents, and future drug development should be encouraged. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.