Data have recently pointed to a possible regulatory function of T-cell immunoglobulin mucin protein 1 (TIM-1) during the alloimmune response. Cross-linking TIM-1 onto CD4+ T cells intensifies proinflammatory cytopathic allogeneic response and inhibits the development of natural and inducible regulatory T cells. The TIM-1 pathway might thus be a potential hurdle to the induction of tolerance in transplantation. Not unexpectedly, blocking the TIM-1 pathway is now emerging as a successful strategy to promote experimental peripheral tolerance.