Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways 1. Wnt/β-catenin is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation 2, 3, but its role in the generation and maintenance of memory T cells is unknown. We found that the induction of Wnt/β-catenin signaling using inhibitors of glycogen-sythase-kinase-3β or the Wnt protein family member, Wnt3a, arrested CD8 + T cell development into effector cells. By blocking T-cell differentiation, Wnt signaling enabled the generation of CD44 low, CD62L high, Sca-1 high, CD122 high, Bcl-2 high self-renewing, multipotent CD8 + memory stem cells with proliferative and anti-tumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of stemness in mature memory CD8 + T cells and have important implications for the design of novel vaccination strategies and adoptive immunotherapies.