Lymphocyte depletion is a commonly used approach in clinical renal transplantation as part of standard induction immunosuppression therapy. It is also increasing being incorporated into new approaches aimed at inducing transplantation tolerance. While the theoretical basis for eliminating alloreactive T cells as a means to prevent rejection and induce tolerance is sound, new evidence suggests that global non-specific deletion may, by promoting the development of memory T cells, actually present a barrier to tolerance induction.