The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their groundbreaking work on regulatory T cells (T-regs). Their discoveries elucidated mechanisms of peripheral immune tolerance, which prevent the immune system from attacking the body’s own tissues. Sakaguchi first identified T-regs in 1995, revealing their critical role in autoimmune disease prevention and immune system balance. Brunkow and Ramsdell contributed complementary findings on the molecular basis of T-reg function, deepening understanding of immune regulation. This seminal work has laid the foundation for therapeutic advances in autoimmune disorders, organ transplantation, and cancer immunotherapy. It challenges prior dogma that immune tolerance depended solely on central thymic elimination and introduces peripheral suppression by T-regs as essential for immune homeostasis. The Nobel Committee recognized these contributions as transformative for the field of immunology and medicine.