Injection of autologous tolerogenic dendritic cells is a promising strategy to diminish the burden of harmful immunosuppression in clinical transplantation. We discuss the immunoregulatory mechanisms triggered by this approach. Tolerogenic dendritic cells have long been associated with decreased antigen-processing capacities. However, different lines of evidence led us to propose that injected autologous dendritic cells may need to process donor antigens from graft passenger leukocytes. It is known that drugs such as calcineurin inhibitors can interfere with antigen processing. Indeed, this issue is of the most importance to rationalize the translation of autologous tolerogenic dendritic cell therapy to the clinic.