The immune system mounts a response to non-self transplanted tissue through a number of mechanisms. The indirect pathway of allorecognition, in which cells of the adaptive immune system recognize MHC alloantigen-derived peptide on self-MHC molecules, has emerged as a potent inducer of allograft rejection. In particular, recent evidence convincingly connects the indirect pathway with chronic rejection, including antibody-mediated and CD8⁺ T cell-mediated rejection. However, the indirect pathway can also promote the generation of regulatory T cells, which have emerged as crucial suppressors of the alloresponse, and hold much promise in the quest for clinical tolerance. An improved understanding of the indirect pathway is likely to bring important benefits to transplant recipients.