Persistence, continuous treatment with a prescribed medication or intervention, is an important, but underrecognized aspect of medication treatment, especially for HIV. In contrast to adherence, which measures the percentage of patient behavior to a prescribed therapy, persistence measures the duration during which a patient remains on a prescribed therapy. Decreased persistence for HIV treatment, or shorter duration on therapy, is associated with increased rates of virological failure, development of antiretroviral resistance, and increased morbidity and mortality. Additionally, frequency and duration of nonpersistent episodes rather than adherence may be a better predictor of clinical outcomes in HIV-infected patients on certain regimens. In this review, we codify the constructs of persistence and adherence, and further define persistence as either patient or regimen persistence. Furthermore, current literature on the clinical consequences of and factors associated with suboptimal persistence is summarized. Finally, methods to measure persistence as well as interventions that may improve persistence and clinical outcomes are suggested.