It is generally accepted that there are two pathways of allorecognition, direct and indirect, that together contribute to allograft rejection. Although it has been suggested that the direct pathway predominates during early acute rejection and that the indirect pathway provides a continuous supply of alloantigen responsible for chronic rejection, the true relative contribution of each pathway to the overall rejection process is still not entirely known. It is clear, however, that any strategies designed to achieve the ultimate goal in transplantation, the induction of tolerance, will need to take into account both pathways. This review seeks to explore the involvement of the direct and indirect pathways of allorecognition on a mechanistic level as it relates to the induction of tolerance. A brief historical perspective is included for each pathway as well as a comprehensive review of the mechanisms felt to be active during tolerance induction.