The immune system, composed of innate and adaptive immunity, orchestrates a complex network of responses to maintain immune equilibrium. Central to this balance are regulatory T cells (Tregs), particularly CD4⁺ regs, which preserve self-tolerance and prevent autoimmunity. Advances in immunoregulation have elucidated key pathways governing Tregs function, including forkhead box P3 (FOXP3) regulation, metabolic dependencies, and interactions with signaling molecules like interleukin (IL)-2 and Notch-1. In addition to CD4⁺ Tregs, emerging research highlights the critical role of Qa-1-restricted CD8⁺ Tregs in promoting transplant tolerance and modulating autoimmune responses. Therapeutic strategies leveraging Tregs, from IL-2-based therapies to genetically engineered chimeric antigen receptor (CAR)-Tregs, have shown promise in modulating allo- and autoimmune responses. This review explores (1) the historical development of immunoregulation, (2) the role of innate and adaptive immune cells in immunoregulation, and (3) the most recent innovations in Treg-based therapies, emphasizing their potential for clinical application in transplantation, autoimmune disorders, and cancer immunotherapy.