Chronic viral infections can appear in two very different forms: those that are typically immunologically contained after acute symptomatic infection, such as Epstein-Barr virus (EBV), and those that predictably lead to persistent viremia and progressive clinical disease. Human immunodeficiency virus (HIV) infection is typical of the latter and has resulted in more than 20 million deaths worldwide. Here we review a remarkable subset of persons infected with HIV who are able to achieve long-term control of viremia and avoid immunodeficiency without the need for antiviral therapy. We review the contributing role of host genetic factors, innate and adaptive immune responses, and viral factors that may contribute to this phenotype. These individuals indicate that as with other potentially pathogenic chronic viral infections, the human immune system is able to fully control HIV and prevent HIV-associated disease, at least in some individuals. Further understanding of the mechanisms whereby this occurs should yield critical insights for prophylactic and therapeutic antiviral interventions.