Transplantation tolerance remains an elusive goal. Despite multiple animal models of tolerance induction using a variety of agents and protocols, it has yet to be achieved in humans with any predictability. In this review, we examine some of the antibodies directed toward T cells that show promise in prolonging graft survival in animal models and in preliminary clinical assessment. Because these antibodies work through multiple pathways, including depletion, downregulation, receptor-ligand blockade, and direct signaling, they have also helped us tease out the various components of long-lived donor-specific tolerance. In particular, we review the role of the thymus in therapies targeted at the peripheral immune system; the importance of the thymus in tolerance induced by anti-CD45RB suggests that central tolerance mechanisms may be more important than previously appreciated.