Host lymphocytes can recognize alloantigens directly on transplanted donor tissue or indirectly after these antigens are processed and presented on host APC. Here, we outline the features of alloresponses that distinguish them from responses to conventional antigens, then we discuss various study systems that have examined where the priming of alloreactive CD4(+) and CD8(+) T cells occurs. Finally, we discuss the implications of recent data which suggest that direct responses originate in the graft itself whereas indirect responses are initiated in the draining lymph nodes.