Many HIV-1 vaccine efforts have heavily emphasized class I-restricted CD8(+) cytotoxic T lymphocytes (CTLs) as a potentially important arm of immunity. Commonly used CTL assays describe only specificity and frequency, and not antiviral effects. However, increasing evidence indicates that CTL antiviral function is determined by the complex interplay of multiple virologic and cellular factors, and thus these measurements are an incomplete reflection of CTL efficacy. Our current understanding of the factors determining HIV-1-specific CTL antiviral efficacy is inadequate to interpret fully the significance of detected CTLs in vaccine and pathogenesis studies. To assess CTLs as a protective immune response, it will be crucial to elucidate these mechanisms and/or devise new assays that directly reflect the interaction of CTLs and HIV-1.