Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways. The Wnt–β-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation^,, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt–β-catenin signaling by 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 promoted the generation of CD44^lowCD62L^highSca-1^highCD122^highBcl-2^high self-renewing multipotent CD8⁺ memory stem cells with proliferative and antitumor 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 major implications for the design of new vaccination strategies and adoptive immunotherapies.