Four human CD8⁺ T-cell subsets, naive (CCR7⁺CD45RA⁺), central memory (T_CM, CCR7⁺CD45RA^–), effector memory (T_EM, CCR7^–CD45RA^–), and CD45RA⁺ effector memory cells (T_EMRA, CCR7^–CD45RA⁺) were compared for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and interleukin-15 receptor expression were low in naive T cells and progressively increased from T_CM to T_EM and T_EMRA. In contrast, the capacity to accumulate in response to T-cell receptor (TCR) or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and Bcl-2 expression. Whereas all TCR-stimulated cells acquired a CD45RA^–CCR7^– phenotype, cytokine-stimulated cells maintained their phenotype with the exception of T_CM cells, which expressed CCR7, CD45RA, and perforin in various combinations. Single CD8⁺ T_CM cells, but not T_EM cells, could be expanded with cytokines, and the obtained clones displayed several distinct phenotypes, suggesting that T_CM cells are heterogeneous. Consistently, CCR4 expression in the CD8⁺ T_CM pool discriminated CCR4⁺ type 2 polarized cells (Tc2) and CCR4^–CTL precursors. Finally, ex vivo bromodeoxyuridine (BrdU) incorporation experiments revealed that memory subsets have different in vivo proliferation rates, with CCR4^–T_CM having the highest turnover and T_EMRA the lowest. These results show that human CD8⁺ memory T-cell subsets have different proliferation and differentiation potentials in vitro and in vivo. Furthermore, they suggest that T_EMRA cells are generated from a T_CM subset upon homeostatic proliferation in the absence of antigen.