Localization of memory CD8⁺ T cells to lymphoid or peripheral tissues is believed to correlate with proliferative capacity or effector function. Here we demonstrate that the fractalkine-receptor/CX₃CR1 distinguishes memory CD8⁺ T cells with cytotoxic effector function from those with proliferative capacity, independent of tissue-homing properties. CX₃CR1-based transcriptome and proteome-profiling defines a core signature of memory CD8⁺ T cells with effector function. We find CD62L^hiCX₃CR1⁺ memory T cells that reside within lymph nodes. This population shows distinct migration patterns and positioning in proximity to pathogen entry sites. Virus-specific CX₃CR1⁺ memory CD8⁺ T cells are scarce during chronic infection in humans and mice but increase when infection is controlled spontaneously or by therapeutic intervention. This CX₃CR1-based functional classification will help to resolve the principles of protective CD8⁺ T-cell memory.