Entry inhibitors represent a new generation of antivirals for the treatment of HIV infection. Several compounds which block the attachment of HIV gp120 to either the CD4 T cell receptor or the CCR5/CXCR4 co-receptors are currently in clinical development. Most of these compounds have different molecular structures and specific mechanisms of action. These agents are eagerly awaited by a growing number of patients carrying viruses resistant viruses to many of the current available reverse transcriptase and protease inhibitors. For enfuvirtide, the first and, so far, only entry inhibitor approved for clinical use, the main mechanism of resistance is the selection of changes within a 10 amino acid segment encompassing residues 36-45 within the HR1 region of gp41. For other entry inhibitors, multiple changes in different gp120 domains (V1, V2, V3, C2 and C4) have been associated with loss of susceptibility to these agents, although in most cases with limited cross-resistance.