Body fat changes and metabolic abnormalities such as hyperlipidaemia and diabetes have been increasingly reported following the successful introduction of highly active antiretroviral therapy (HAART). These side effects were attributed initially to the use of protease inhibitors (PIs). As a consequence, a series of trials were conducted where patients with well-controlled HIV viraemia either continued on PIs or were switched to a simplified maintenance therapy (SMT) without PIs. Evidence from these trials is still insufficient to show that switching from PIs to either abacavir, nevirapine or efavirenz is safe. However, patients with suboptimal pre-HAART treatment are at increased risk of virological failure if switched to an SMT. Patients switched from PI regimens tend to stay longer on an SMT and those switched to abacavir show a reduction in total cholesterol, but there is no evidence of any additional benefit from non-PI-based SMT. There is a clear need for a better understanding of HAART-related lipodystrophy and metabolic toxicity, and pharmacogenetic tests to identify those patients most at risk. The advent of simpler formulations for all drug classes, and new PIs with less metabolic toxicity, is likely to reshape completely the role of SMT.