Endogenous regulatory T cells (T reg) play a central role in the control of excessive or misdirected immune responses against self or foreign Ags. To date, virtually no data are available on the nature of the molecules and signals involved in the trafficking and retention of T reg in tissues where regulation is required. Here, we show that expression of α E β 7 integrin is necessary for the homing of T reg at site of Leishmania major infection. The vast majority of T reg present in the dermis at steady-state conditions or during L. major infection express the α E chain (CD103) of α E β 7. Genetically susceptible BALB/c mice that lack CD103 become resistant to infection, a phenotype that is associated with a poor capacity of T reg to be retained in the infected site. Such susceptible phenotype can be restored when T reg from wild-type mice were transferred in CD103−/− mice. The central role of CD103 in T reg retention was further demonstrated by usage of blocking Abs against CD103 and the transfer of T reg purified from CD103−/− mice. Our results strongly suggest that this molecule is induced and maintained on T reg following or just prior to their arrival in tissues. Furthermore, the expression of CD103 and the subsequent retention of T reg in tissues is highly regulated by their exposure to Leishmania Ag and the level of activation of the APCs they encounter. Thus, CD103, by controlling T reg retention, can contribute to the outcome of chronic infection by Leishmania.