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The main objective of this review is to briefly highlight how we gradually came to understand regulatory T cells (Tregs) and forkhead box p3 (FoxP3) biology, including their function and regulation. We will also discuss how this knowledge is being translated into the clinical setting and the significant challenges that need to be overcome.CD4+FoxP3+ Tregs are key players in immune regulation. Their deficiency and dysfunction have been implicated in the pathogenesis of many autoimmune diseases. This has led towards extensive work across the years to figure out the biology and suppressive mechanisms of these cells. Furthermore, Tregs’ ability to suppress immune responses makes the idea of their utilization in adoptive immunotherapy appealing. Work has been underway to establish ideal methods to integrate Tregs into the management of autoimmune diseases and alloimmunity, either by treatment with IL-2 or infusion of ex-vivo expanded Tregs. Despite Tregs’ scarcity and increased tendency for Activation-induced cell death, many groups have developed effective methods to expand them ex vivo.Although clinical trials are ongoing to test the safety and efficacy of regulatory cells in transplant recipients, it is vital to continue exploring the cellular and molecular mechanisms that control their stability and homeostasis.