After over a decade of eclipse, suppressor T (Ts) cells have regained a reputation as key controllers of peripheral immunological self-tolerance. This Opinion focuses on recent advances in understanding the trafficking and tissue localization of CD25⁺CD4⁺ T cells, the best characterized population of naturally occurring Ts cells. Their distinct homing preferences and selective responsiveness to specific chemokines help in defining their role in physiological and pathological immune responses, and could offer the possibility of developing novel therapies for immunomodulation.