Entry inhibitors are a new class of drugs for the treatment of HIV infection. Enfuvirtide is the first compound of this family to be approved for clinical use. It blocks HIV fusion to host cells. It is a synthetic peptide that mimics an HR2 fragment of gp41, blocking the formation of a six-helix bundle structure which is critical in the fusion process. Enfuvirtide is a good therapeutic option as rescue therapy in combination with other active antiretrovirals and works against different HIV-1 variants, including all group M subtypes and group O. However, it is not active against HIV-2. The main mechanism of resistance to enfuvirtide depends of the selection of changes in a 10-amino acid domain between residues 36 to 45 in the HR1 region of gp41. Single and double mutations in this region have been shown to result in high-level resistance to enfuvirtide. A negative impact of enfuvirtide-resistance mutations on viral fitness has been postulated, since resistance mutations tend to disappear soon after drug discontinuation and because immunologic benefits have been noticed despite virologic failure in patients undergoing enfuvirtide treatment.