T cells recognize nominal antigens as processed peptides p: e~ ented by self major histocompatibilit 3, complex (MHC! molecules (/VHC restriction). An important step in the understanding of alioveacdviry came with the discover 3-that T cells car, engage and respond~(, aliogeneic MHC molecules directly (Fig. 1). Thi~(orm of anttgen recognition, termed direct presentation or the direct pathway, is reapon~ ible for the strong prolifcraative resFonse to a! loantigens seen in vitro and the events leading to the early acute rejection of MHC-mismatched skin g-afts. A sevond route for the presentation of allogeneic MHC molecules also txi, ts, the indirect pathway. For recogn; tion via this route, ailogeneic MHC molecules are p,-ocessed and presented by recipient antigen-presenting ceil:(APC) in the same manner as for T-cell recognition of any nominal antigen or indeed mismatched minor histocompatibility antigens (Fig. 1). In general, peptides presented:,....~: _~:,,,•-......... n with MHC class I molecules are processed aid the e, dogenc us pathway~ m'3 d~ ose presented by MHC class il molecules are processed via: he exogenous pathway, although cross-talk between the pathways can occurk Alloantigens shed from a gra~ arc most likely to be treated as exogenous antigens i994, Elsevier Science by recipient APC, therefore CD4+ T cells recognising allopeptides bour~ d to MHC class ii molecules may dominate the response to a! loantigen presented by the indirect pathway. Tb-multiplicity of epitopes that may be generated Lv: he processing and indirect presentation of MHC mo! ccules could provide a powerful way oi amplifying the reiection response. Self restricted, indirect presentation of allopeptides as a pathway for stimulating and/or~ mplifying alloresponses has therefore received much~ rtention in recent years, due to its potential impertance in the event, leading to the rejecrion of allografts and xe~ ografts, antibody forma¢ ion, and the induction of,::; responsiveness to alloant~ gev. In this review wc~ vill summarise the experimental evidence supporting the view that indirect presentation of allopeptides can occur both in vitro and in vivo and discuss the s~ tuations in transplantation where indirect presentation of alloan: igens may play an important rote.