For many years the direct stimulation of T cells in response to donor MHC antigens expressed on donor antigen-presenting cells has been the focus of transplantation immunology. Indirect recognition in response to peptides of donor antigens presented by self MHC molecules on recipient antigen-presenting cells has not genrally been considered an important feature of graft rejection. Recent evidence suggests that indirect responses may be more important than previously considered and the new emphasis on indirect pathways in allograft rejection has raised new issues, many of which are unresolved