Combined antiretroviral therapy (cART) has evolved considerably over the past decades leading to a better control of human immunodeficiency virus replication. Recently, regimens have evolved so as to simplify dosing frequency and reduce pill burden to improve adherence. Several national and international guidelines suggest antiretroviral (ARV) regimen simplification as a method of improving adherence. Decreased cART adherence has been associated with both patient-related factors and regimen-related factors. Adherence rates are statistically higher when simpler, once-daily (OD) regimens are combined with smaller daily regimen pill burdens. The avoidance of selective non-adherence, where a patient takes part of a regimen but not the full regimen, is a further potential benefit offered by single-tablet regimens (STRs). Simplification of cART has been associated with a better quality of life (QoL). Although tempered by other factors, better adherence, higher QoL and patients' preferences are all key points which might combine to assure long-lasting efficacy and durability of cART. All studies underlined the favorable tolerability profile of newer STRs. Three STRs are currently available. Tenofovir (TDF) plus emtricitabine (FTC)/efavirenz (EFV) was the first OD complete ARV regimen available as a STR. TDF plus FTC/rilpivirine is a second-generation STR. The most recently approved STR, TDF plus FTC/cobicistat/elvitegravir, is the first non-nucleoside reverse transcriptase inhibitor-based STR. All of them have shown excellent efficacy; safety and tolerability have been improved by more recent formulations. Several other STRs are anticipated both combining completely different drugs, abacavir (ABC) plus lamivudine (3TC)/dolutegravir, utilizing innovative formulations of older drugs, tenofovir alafenamide fumarate, or taking advance of bioequivalent drugs, lamivudine (3TC) plus ABC/EFV. The future challenge would be to develop completely alternative STRs (including for example protease inhibitors or new molecules) to extend the advantages of simplicity to heavily pre-treated individuals.