Presently, it is thought that virus-specific T cells play a major role in restricting lentiviral replication and determining the rate of disease progression in humans. However, it remains unclear why this restriction fails in the majority of infected individuals. The major exception is a rare subgroup of HIV-infected long-term nonprogressors (LTNPs) who have been infected for approximately 20 years yet maintain normal CD4(+) T-cell counts and less than 50 copies of viral RNA/mL of plasma. Although virus-specific cellular (CD4(+) and CD8(+) T lymphocytes) immune responses have been shown to exert some degree of in vivo control of HIV replication, the precise correlates of protective immunity differentiating LTNPs from patients with progressive disease remain unknown. A greater understanding of the components and magnitude of an effective immune response to HIV is an important step toward the development of effective vaccines and immunotherapies.