Organ allografting is now widely practised.  The full potential of this therapy however has not been realised. The need to administer systemic immunosuppressants in order to prevent graft rejection, renders the recipient more susceptible to infection and cancer. Furthermore, these drugs are of themselves often toxic. Hence, organ allografting is generally only performed in life threatening situations, despite its potential value in alleviating the symptoms and complications of a number of diseases. In an effort to decrease the need for systemic immunosuppression, and increase the applications of organ transplantation, we and others have focused on immune modulation of the graft and its microenvironment. In this review we will discuss three such approaches which are under investigation in our laboratory: vaccination against immunogenic passenger leukocytes carried within the graft but not required for graft function, engineering of the graft to secrete immunomodulatory molecules into the graft microenvironment, and  sequestration of the graft behind a physical barrier.