Resistance to protease inhibitors (PIs) often appears as a result of changes at codons within the protease gene, which differ from one drug to another. When PIs are boosted with low doses of ritonavir, multiple mutations at the protease are required to reduce significantly the antiviral activity of these compounds. Moreover, mutations at gag cleavage sites may restore the loss of viral fitness caused by the selection of specific PI resistance mutations. In respect to entry inhibitors, a new class of compounds already in phase II/III clinical trials, resistance may emerge as a result of mutations outside the pol gene. Loss of susceptibility to agents that block virus attachment or the interaction with co-receptors often select HIV strains with mutations in the gp120 envelope-coding region. In contrast, agents that target gp41-dependent fusion select for HIV variants with mutations in the gp41 envelope gene.