The current standard of care in transplantation reliably achieves acceptable graft and patient survival but still depends on life long immunosuppression in most patients. Current strategies employ medications that, in general, inhibit distal events mediating rejection, namely T cell activation and cytotoxicity. They do not typically interfere with initial allorecognition or the factors that influence the direction of an immune response (towards cytotoxicity as opposed to anergy or regulation). Given the exponential amplification of immune responses, these proximal targets may be more efficient in preventing rejection. Recent laboratory investigations have identified several approaches, e.g., costimulation blockade, depletion, and hematopoietic chimerism, that influence the initial stages of the alloimmune response, or establish self-perpetuating means of eliminating rejection without chronic immunosuppression. This manuscript reviews methods of immune manipulation that the authors view as promising for future exploitation and transfer to the clinic. These therapies are similar in that they are viewed as attempts to influence the ability of the body to mount an immune response and its subsequent direction, as opposed to supplying late effector phase inhibition. While it is recognized as unlikely that any one therapy will universally lead to tolerance, the authors propose that these concepts will make immunosuppressive drug minimization more readily successful.