Combination antiretroviral therapy (cART) was one of the greatest achievements in medicine in the twentieth century. It has rapidly evolved during the last 10 years from suboptimal monotherapy to an effective triple therapy that can change the natural history of HIV-1 infection from a deadly disease to a chronic, manageable condition. However, a dreadful toll of long-term toxicity was experienced by HIV-1-infected patients in the cART era. We have recently entered in a new phase of cART, in which efficacy has been increased and toxicity minimized. Currently, the greatest challenge is to make cART available to everybody who needs it with the future prospects of HIV-1 eradication.