The circulating precursor cells that give rise to human resident memory T cells (T _RM ) are poorly characterized. We used an in vitro differentiation system and human skin–grafted mice to study T _RM generation from circulating human memory T cell subsets. In vitro T _RM differentiation was associated with functional changes, including enhanced IL-17A production and FOXP3 expression in CD4 ⁺ T cells and granzyme B production in CD8 ⁺ T cells, changes that mirrored the phenotype of T cells in healthy human skin. Effector memory T cells (T _EM ) had the highest conversion rate to T _RM in vitro and in vivo, but central memory T cells (T _CM ) persisted longer in the circulation, entered the skin in larger numbers, and generated increased numbers of T _RM . In summary, T _CM are highly efficient precursors of human skin T _RM , a feature that may underlie their known association with effective long-term immunity.