The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their discovery of regulatory T cells (Tregs), a critical mechanism of peripheral immune tolerance that prevents autoimmune attacks. Sakaguchi first identified CD4+CD25+ T cells that suppress autoimmunity, overturning previous beliefs that central tolerance in the thymus was the sole mechanism. Brunkow and Ramsdell provided complementary evidence elucidating the molecular basis underlying Treg function. This foundational work reshapes therapeutic approaches for autoimmune diseases, cancer, and transplantation, focusing on enhancing or modulating Treg activity.