CTL express lytic proteins that mediate the cytolysis of virus-infected cells. In this study, cytolytic transcriptional profiles were determined for individual CTL responding to influenza A virus and HSV-1. During acute infection, influenza-specific CTL in the spleen and respiratory airways displayed highly activated cytolytic profiles, as did HSV-1-specific CTL localized in the spleen, skin, and dorsal root ganglia (DRG). In contrast, memory CTL dramatically down-regulated cytolytic molecule transcription. This occurred for both lymphoid (spleen) and tissue-resident (skin and/or lung) memory CTL. In contrast, HSV-1-specific CTL localized in the dorsal root ganglia in the presence latent HSV-1 Ag did not down-regulate cytolytic molecule transcription. Therefore, both lymphoid and tissue-resident memory CTL down-regulate cytolytic molecule transcription following virus clearance unless localized Ag is present.