The field of transplantation has developed based on two principles: allografts are rejected because they express foreign antigens, and the immune system must be suppressed to prevent rejection. Recently, in vitro and in vivo experimental evidence has accumulated that calls both of these beliefs into question. This article reviews an alternative approach to transplantation that focuses on tissue injury as the instigator of graft rejection and employs physiological mechanisms of tolerance to avoid graft loss. Methods that allow for defense against infectious microbes while at the same time allowing for graft survival are proposed. In particular, the rationale behind the use of anti-CD154 antibody treatment is highlighted. A model is introduced that takes into consideration the experimental successes seen with anti-CD154 therapies.