As of 2008, more than 33 million adults and children have been estimated to be living with human immunodeficiency virus (HIV). Among them are rare patients (<0.5%) who have remained clinically well without antiretroviral therapy after almost 20 years of infection. They maintain stable CD4 cell counts and suppressed HIV replication to levels comparable with those measured in patients receiving combination antiretroviral therapy. No known epidemiologic or behavioral factors are predictive of untreated, nonprogressive HIV infection; however, host genetics and immune response factors, most specifically HLA antigen class I–restricted HIV-specific CD8 T cells, appear to be primarily responsible for this remarkable phenotype in a majority of these individuals. These patients offer hope that durable control of HIV infection is possible and can provide important insight to inform the development of the next generation of HIV/AIDS vaccines and immune-based therapies. This article reviews clinical features of these unique patients and discusses them in the context of nonprogressors enrolled in other cohorts. Potential mechanisms underlying nonprogressive HIV infection and scientific discoveries, facilitated by the participation of these patients in clinical trials, of relevance to the design of an efficacious HIV/AIDS vaccine are also highlighted.