Current strategies for immunosuppression following organ transplantation focus on the prevention of acute rejection. As new generations of immunosuppressants have been developed, acute rejection rates have diminished markedly. The new challenge, then, is to prevent the devastating complications of chronic rejection, which have remained largely unchanged over the decades. The process of chronic rejection is a complex one, and it is likely that most, if not all, components of the immune system play some role in the long-term, smoldering failure of organs following transplantation. Through a better understanding of their individual contributions as well as interactions, new strategies may be developed to overcome this problem. We present here an overview of the major immune components thought to be involved in chronic rejection.