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, the direct antidonor alloresponse diminishes with time after transplantation, possibly due to the tolerogenic effects of alloantigen presentation by the parenchymal cells of the transplant. In contrast, the indirect alloresponse is likely to be permanently active, due to traffic of recipient dendritic cells (DCs) through the graft. The challenge that this poses in the pursuit of clinical transplant tolerance is how to induce tolerance in T cells with indirect allospecificity.