The dramatic improvement seen in the latest years in the prognosis of HIV infection has been threatened by long-term toxicities of antiretroviral drugs. Nucleoside analogs remain the cornerstone of antiretroviral therapy, but these compounds seem to produce mitochondrial damage leading to a broad range of side effects, which depend of the organ/tissue affected. Among those toxicities are of particular concern lipoatrophy and hyperlactatemia syndromes. This review will focus on the pathogenesis of mitochondrion damage caused by nucleoside analogs and its clinical consequences, particularly in respect to body-shape changes.