An area of considerable interest in current transplantation immunology is the role of costimulatory molecules in the development of the immune response. One specific costimulatory receptor:ligand interaction that has been the object of extensive investigation is that of CD40:CD154. This interaction has been implicated in T cell and antigen-presenting cell activation, and in the pathogenesis of allograft rejection. This review examines recent progress made in our understanding of these important costimulatory molecules, and their potential relevance to therapeutic immunosuppression.