Until recently, the vigorous T cell response via the direct pathway has overshadowed studies involving the indirect pathway. Thus, while the direct pathway has previously been considered to be the main driving force in alloimmune responses, there is an increasing body of data to support a prominent role of the indirect pathway in transplant rejection. Most importantly, while the direct anti-donor alloresponse diminishes with time after transplantation, the indirect alloresponse is likely to be permanently active due to traffic of recipient dendritic cells (DCs) through the graft. Consequently, the future challenge in the induction of allograft tolerance is to design interventions that will target the cells involved in the indirect pathway, especially the T cells with indirect allospecificity.