T-cell depletion strategies are an efficient therapy for the treatment of acute rejection after organ transplantation and have been successfully used as induction regimens. Although eliminating whole T cells blocks alloreactivity, this therapy challenges the development of regulatory mechanisms because it depletes regulatory cells and modifies the profile of T cells after homeostatic repopulation. Targeting T-cell subpopulations or selectively activated T cells, without modifying Treg cells, could constitute a pro-tolerogenic approach. However, the perfect molecular target that would be totally specific probably still needs to be identified. In this study, we have reviewed the biological activities of broad or specific T-cell depletion strategies as these contribute to the induction of regulatory cells and tolerance in organ transplantation.