Dual therapy refers to combinations of two antiretroviral drugs applied in different clinical settings; they are considered and studied due to possibly reduced drug toxicities. In antiretroviral-naive patients, dual combinations have lower virologic efficacy than standard therapy; the sole efficacious regimen is lamivudine plus lopinavir/ritonavir. Due to a higher possibility of virologic failure, these regimens are generally not allowed in this clinical setting. In antiretroviral-experienced patients, dual regimens are examined in studies with a small sample size, centered on clinical practice, and should be ritonavir-boosted protease inhibitor-based. These combinations have a good virological efficacy; combinations with the integrase inhibitor raltegravir have small sample size and demonstrated efficacy only with etravirine. Virological aspects involving dual therapy should always consider genetic barriers, particularly in simplification strategies, and ritonavir-boosted protease inhibitors are mandatory. As far as immunological aspects are concerned, nucleoside reverse transcriptase inhibitor-sparing regimens have some encouraging data, probably due to the bone marrow toxicity of this class. Combinations with maraviroc were effective in reducing inflammation, but data about immunological recovery are conflicting. The choice of regimen should focus on specific class toxicity since dual regimens are studied in particular for improving safety and tolerability. This review will analyze different dual regimens in the clinical setting, with a peculiar focus on ameliorating toxicities and improving quality of life.