The development of highly active antiretroviral therapy has improved life expectancy and reduced progression to acquired immunodeficiency syndrome in human immunodeficiency virus (HIV)-infected patients. However, resistance to currently available classes of antiretroviral drugs has become a problem, limiting the options for patients with advanced disease who have been heavily treated. Enfuvirtide (T-20; ENF), a synthetic peptide, is the first of a new class of antiretrovirals that block entry of virus into host cells. ENF interferes with conformational changes required for membrane fusion and injection of virus into the host cell. Optimal treatment of HIV infection will likely require combinations of drugs that target novel stages of HIV type 1 entry and replication.