The balance between the immune system and its metabolism is becoming an effective therapeutic alternative in various inflammatory diseases, including organ transplantation. The interaction between the immune and metabolic pathways play a critical role in dictating disease pathology and progression, and the differences in the bioenergetic demands between immune cells enable them to differentiate into effector and regulatory cells. Recent studies have suggested that changes in intracellular metabolic programs control T cell proliferation and differentiation into T effector (Teffs) or T regulatory cells (Tregs), and metabolic differences between Tregs and Teffs help shift the balance toward a more specific immune tolerance in organ rejection. Controlling the fate of naïve T cells by metabolites (cellular metabolism) rather than the more toxic molecular interventions are of great interest in cancer, autoimmunity, and organ transplantation. In this review, we discuss major metabolic pathways that influence the proliferation, differentiation, and stability of Tregs to rescue organ transplants from associated injuries and chronic rejection.