CD8+ T-cells with cytotoxic (CTL) activity play a pivotal role in controlling viral infections. Although most patients chronically infected with HIV have CTL response against the virus, for reasons that are not well understood this response is not able to successfully control viral replication. The crucial role of this type of response has been clearly demonstrated in the setting of acute infection using the simian model of AIDS, in which a strong CTL response develops, supporting its role in humans. This approach has been possible due to the development of new assays to quantify CTL activity with great sensitivity and specificity. The interaction of CTL response and HIV during this acute stage of infection is crucial, since it most probably determines the viral set-point and thus the rate of HIV disease progression. In the setting of chronic HIV infection, the use of tetrameric complexes and IFN-gamma production assays have made it possible to investigate the different functional aspects of these cells and have also facilitated the evaluation of this response in large patient populations. Defects in cytokine production and in perforin expression have been found, as well as alterations in phenotypic maturation and a low proliferation of these cells. All these findings have been cited to explain the inability of CTLs to efficiently control virus replication. Nonetheless, accumulating evidence points toward an important role for CTL response in the partial containment of HIV replication in chronic infection. An especially strong support for this observation derives from studies analyzing the selective pressure exerted by the immune response over viral evolution. Very recently, longitudinal and cross-sectional studies in large populations of patients have demonstrated that viral evolution is in part driven by HIV-specific T-cell responses.