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.