Highly active antiretroviral therapies (HAART) provide sustained viral control in most patients, but many of these regimens are restricted by complex dosing, drug-drug interactions and toxicities. Numerous strategies of simplified treatment have been explored in order to improve patient quality of life and adherence to treatment, as well as to manage drug-related toxicities while maintaining viral suppression. The first simplification strategy involved switching from protease inhibitors (PIs) to non-nucleoside reverse transcriptase inhibitors (NNRTIs), with an additional benefit on lipid metabolism. The development of once-daily drugs or co-formulated combinations has successfully been used to further simplify treatment. However, studies assessing triple nucleoside regimens have shown a higher frequency of viral failure in comparison with standard HAART, mainly in patients with previous sequential suboptimal treatments. Finally, NRTI-sparing approaches, consisting of NNRTI+PI combinations or monotherapies with boosted PIs, are alternatives to avoid NRTI-related mitochondrial toxicities. An accurate analysis of each patient's history will be necessary in each case to determine whether a simplification strategy is appropriate.