Induction of specific immune tolerance to grafts remains the sought‐after standard following transplantation. Defined by expression of the Foxp3 (forkhead box protein 3) transcription factor, the regulatory T‐cell (Treg) lineage has been noted to exert potent immunoregulatory functions that contribute to specific graft tolerance. In this review, we discuss the known signals and pathways which govern Treg development, both in the thymus and in peripheral sites, as well as lineage maintenance and homeostasis. In particular, we highlight the roles of T‐cell receptor signaling, CD28 costimulation, and signals through phosphatidyl inositol 3‐kinase (PI3K) and related metabolic pathways in multiple aspects of Treg biology.