Interleukin-7 (IL-7), the principal cytokine implicated in thymopoiesis and peripheral T-cell homeostasis, is presently under evaluation in human diseases characterized by persistent lymphopenia. Unexpectedly, before the eventual IL-7-driven T-cell expansion, all treated patients showed a profound T-cell depletion 24 hours after injection. The current study uses the rhesus macaque model to investigate the mechanisms involved in this IL-7-induced T-cell depletion. We identify a new critical function of IL-7 that induces massive and rapid T-cell migration from the blood into various organs, including lymph nodes, parts of the intestine, and the skin. This homing process was initiated after the induction of chemokine receptor expression by circulating T cells and the production of corresponding chemokines in target organs. Finally, we demonstrate that the IL-7-induced cell cycling is initiated within these organs before T cells migrate back into the bloodstream, indicating that T-cell homing is required for in vivo IL-7 function.