CD8(+) T cells have been described as being naive or one of 4 antigen (Ag)-experienced subtypes representing a continuum of differentiation and maturation: T memory stem cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cells. In mice, adoptive cell transfer of less-differentiated naive T cells, T memory stem cell, and central memory T cell subsets have consistently demonstrated superior in vivo expansion, persistence, and antitumor capacities relative to the more differentiated effector memory T cell and effector T cell subsets. Retrospective analyses from human adoptive cell transfer trials have confirmed that transfer of less-differentiated T-cell subsets is highly correlated with objective clinical responses. These findings, combined with the recent ability to convey de novo Ag reactivity with high efficiency through genetic engineering of exogenous T-cell or chimeric Ag receptors, now challenge the field with 3 important questions: (1) how should less-differentiated T-cell subsets be isolated for human clinical trials?; (2) what is the best means of expanding T cells ex vivo in such a way as to not corrupt the beneficial traits of the younger subsets?; and (3) is it necessary to physically separate younger subsets from their more differentiated counterparts? Answering these questions will allow for the rational development of the next generation of highly effective and potentially curative T-cell therapies for the treatment of cancer.