Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin α_Eβ₇ discriminates distinct subsets of murine CD4⁺ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. α_E⁻CD25⁺ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, α_E-positive subsets (CD25⁺ and CD25⁻) displayed an effector/memory phenotype expressing high levels of E/P-selectin–binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, α_E-expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.