The human immunodeficiency virus (HIV) exhibits extensive heterogeneity due to its rapid turnover, high mutation rate, and high frequency of recombination. Its remarkable genetic diversity plays a key role in virus adaptation, including development of drug resistance. The increasing complexity of antiretroviral regimens has favored selection of HIV variants harboring multiple drug resistance mutations. Evolution of drug resistance is characterized by severe fitness losses, which can be partially overcome by compensatory mutations or other adaptive changes that restore virus replication capacity. Recent reports have addressed the impact of drugresistance mutations on viral fitness. Methods include in vitro estimates based on the determination of viral replication kinetics, viral infectivity in single-cycle assays and growth competition experiments; as well as estimates of the relative fitness of viral populations in vivo calculated from standard population genetics theory. This review focuses on the effects in viral fitness of mutations arising during treatment with reverse transcriptase and protease inhibitors, and the molecular mechanisms (including compensatory mutations) that improve the viral fitness of drug-resistant variants.