CD4⁺CD25⁺ regulatory T (T_R) cells are essential negative regulators of multiple immune functions. Their development and function are critically dependent on the forkhead transcription factor Foxp3. IL-2R-derived signals are also required for their maturation and/or proliferation. Expression of the TNF receptor family member GITR appears to define this naturally arising, thymically derived lineage more accurately than CD25. T_R cells suppress virtually all forms of immune responsiveness investigated to date, including both adaptive and innate immunity. T_R cells are capable of robust antigen-driven proliferation in vivo, and may participate in clonal expansion in response to infection, similar to all other adaptive immune lineages.