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The use of a combination antiretroviral therapy (cART) has changed dramatically the prognosis and the life expectancy of people living with HIV. The current treatment guidelines continue the convention of preferred cART based on combining a dual nucleoside reverse-transcriptase inhibitor (NRTI) backbone with a third "anchor" agent, such as a ritonavir (r)- or cobicistat (c)-boosted protease inhibitor (PI), a non-NRTI (NNRTI), or an integrase inhibitor (INI) boosted or unboosted. However, due to toxicities of NRTIs, sparing NRTI regimen has been studied for a long time with moderate success due to low efficacy (especially in patients with high viral load and low CD4) compare to standard triple therapy. New strategy with lamivudine (3TC) plus a boosted PI or INI showed promise results and indicated that modern two-drug regimens might now, in fact, become a reliable treatment for HIV-infected naïve patients. This article discusses recent data from dual therapy studies in naïve HIV-infected patients and the challenges behind this strategy.