Current treatment for HIV is characterized by highly potent oral antiretroviral medications, which are well tolerated, resulting in outstanding rates of virologic suppression in patients who are adherent to therapy. Despite the marked improvement in therapeutic options, limitations to therapy still exist including reliance on daily adherence, long-term toxicity of medications, drug–drug interactions, long-term effects of HIV even in the setting of viral suppression, high lifetime cost of treatment, and limited options for some patients with multiclass resistance. Emerging alternative treatment strategies include nucleoside reverse transcriptase inhibitor-sparing or limiting regimens and long-acting injectable combination therapy.