An ability to modulate three distinct yet inter-related immune processes is required for successful allogeneic hematopoietic stem cell transplantation (HSCT): reduction in graft-versus-host reactivity that initiates graft-versus-hostdisease (GVHD), inhibition of host-versus-graft reactivity that causes allograft rejection, and enhancement of graftversus- leukemia (GVL) and graft-versus-tumor (GVT) effects that primarily account for the curative capacity of allogeneic HSCT. Each of these inter-related processes is susceptible to modulation by sirolimus, which restricts receptor and nutrient mediated signaling in multiple cell types through inhibition of the central regulatory molecule, mammalian target of rapamycin (mTOR). In experimental models, sirolimus beneficially: (1) prevents GVHD; (2) prevents graft rejection; and (3) directly mediates anti-tumor responses in tumors with constitutive activation of the phosphoinositide-3 kinase (PI3K) pathway that lies upstream to mTOR. However, sirolimus detrimentally may: (1) abrogate GVL and GVT effects; (2) reduce function of APC populations; and (3) inhibit hematopoiesis. As such, utility of interventions that inhibit mTOR will depend upon the balance of beneficial vs. detrimental effects generated. Recent clinical trials indicate that sirolimus can indeed yield a favorable balance to this equation, as the drug appears to prevent GVHD without marked impairment of alloengraftment or anti-tumor effects. However, sirolimus therapy is limited by drug toxicity and a relatively narrow therapeutic window. This limitation may be overcome in part through in vitro usage of sirolimus for allograft T cell engineering in clinical trials now in progress.