One method of inducing tolerance to allografts is the use of lymphocyte depletion. This strategy has demonstrated remarkable efficacy in clinically relevant large-animal models of allotransplantation. Although the mechanism by which therapeutic lymphocyte ablation promotes tolerance remains unclear, continued research is gradually characterizing its effects on the immune system. Significant advances are also being made in our ability to develop and deliver effective lymphocyte-depleting agents. This review examines recent progress in our understanding and application of this paradigm of tolerance induction.