Acute rejection during the first year post-transplant is a key predictor of graft survival after renal transplantation. Use of induction therapy with a lymphocyte-depleting agent or an interleukin-2 receptor (IL-2R) antagonist can provide effective protection against rejection in the first critical weeks and months post-transplant. Polyclonal lymphocyte-depleting antibodies are associated with a low incidence of rejection but evidence of their benefit in terms of graft survival is lacking. Thymoglobulin appears to offer superior graft outcomes compared with generic antithymocyte globulin (ATG). The most frequent adverse events are symptoms of cytokine release syndrome, leukopenia, thrombocytopenia, and tachycardia; data on whether polyclonal antibody use increases the risk of lymphoma are conflicting. Muromonab CD3 (OKT3), a monoclonal lymphocyte-depleting antibody, is efficacious but a high incidence of cytokine release syndrome and increased risk of post-transplant lymphoproliferative disease have limited its use. Following their recent introduction, the IL-2R antagonists basiliximab and daclizumab are now used widely, after randomized trials demonstrated that addition to calcineurin inhibitor-based therapy significantly reduced acute rejection by approximately 30-40%. Meta-analyses and registry analysis suggest that addition of an IL-2R antagonist may improve graft survival. The safety profile of IL-2R antagonists is indistinguishable from placebo, with no apparent difference in incidence of infection or post-transplant lymphoproliferative disease. IL-2R antagonists and polyclonal lymphocyte-depleting antibodies (with delayed cyclosporine) offer equivalent efficacy in standard-risk populations; in a trial of high-risk patients, acute rejection rate and graft outcomes were improved with Thymoglobulin. Tolerability is superior with IL-2R antagonists: cytokine release syndrome and hematologic disturbances (notably leukopenia) are significantly more frequent with polyclonal antibodies. Cytomegalovirus infection may also be more common with lymphocyte-depleting antibodies. Thus, in patients at high risk of graft loss, Thymoglobulin may be the preferred choice for induction therapy, while for all other patients, IL-2R antagonists should be considered first-line choice for induction therapy.