Application of advanced molecular techniques and novel animal models has provided new insights into basic mechanisms underlying clinical transplantation. Investigations in diverse areas, including graft rejection and tolerance, autoimmunity and infectious diseases, have revealed increasing complexity of the mechanisms controlling immune function, notably at the interface of the innate and adaptive immune systems and within secondary lymphoid organs. New roles have been identified for NK and dendritic cells, B-lymphocytes and for Th17 and regulatory T cells, notably in novel animal models of costimulatory blockade and tolerance. Confirmation of these observations will be needed in normal animals and in humans undergoing organ and cell transplantation. The impact of the microbiome, of vaccines, and of antimicrobial therapies on immune memory and reconstitution after lymphocyte depletion is beginning to be defined.