One approach to target the long-term metabolic toxicity and disfiguring body-shape changes associated with antiretroviral therapy is to switch one component of a regimen to an alternative drug, usually from a different class of antiretrovirals. Most commonly, substitutions have involved protease inhibitors, but the thymidine analogue nucleosides, especially stavudine, have been investigated more recently. Certain trends from these studies have emerged. First, if the patient has had sustained viral suppression, switching therapy is generally virologically safe. Second, metabolic disturbances, such as insulin resistance and dyslipidemia, appear to be at least partially reversible. Substitution of other agents for protease inhibitors has not been associated with reversal or improvement in fat redistribution. Studies in which thymidine analogue reverse-transcriptase inhibitors have been switched have reported modest improvements in peripheral lipoatrophy. Larger, controlled, long-term studies and a more standardized approach to definition of metabolic and morphological abnormalities are needed.