Immunodeficient individuals are susceptible to opportunistic infection. While stem cell transplantation can restore a functional immune system, T cells are slow to recover and limited in eliciting adaptive immune responses. Approaches to selectively enhance T cell function have focused on boosting thymopoiesis to generate new T cells or expanding existing T cells. By taking advantage of the role of Notch signaling in T cell development, we have developed an in vitro system able to generate large numbers of progenitor T cells from human hematopoietic stem cells. Here, we discuss this in vitro system and its implications for the potential treatment of T cell immunodeficiency.