Resistance to antiretroviral drugs is associated with reduced treatment options and, therefore, increased risk of disease progression or death. Despite the main goal of antiretroviral therapy should be achievement of complete suppression of HIV replication, the accumulation of resistance mutations in patients with multiple treatment failure makes this objective often difficult, or even impossible to obtain. Thus, clinicians should be aware about the complex relationship between drug pressure and viral replication capacity and about some potential advantages related to antiretroviral drug resistance. The two main biological mechanisms that can be at the origin of these clinical benefits are: reduction of viral fitness and viral hypersusceptibility. The term “fitness indicates the ability of HIV to maintain high rate of replication capacity in presence of antiretroviral drugs. Consequently, replication capacity, high in presence of wild type virus, tends to decrease when HIV must adapt its enzymes to work in presence of drugs. A reduction of viral fitness is observed in patients harbouring mutations conferring resistance to all the three classes of antiretroviral drugs currently in use. Particularly, the effects on reduction of replication capacity related to M184V mutation in reverse transcriptase are analyzed. Viral isolates with reduced susceptibility or resistance to some antiretroviral drugs may exhibit significant increased susceptibility to other drugs acting on the same enzyme. This phenomenon is known as hypersusceptibility and can be demonstrated in vitro by phenotypic assays. Phenotypic hypersusceptibility has been demonstrated for all three drug classes. Particularly, NNRTI hypersusceptibility, associated with NRTI mutations, is analyzed and discussed.