The ability of stem cells to differentiate into various different cell types holds great promise for the treatment of irreversible tissue damage that occurs in many debilitating conditions. With stem cell research advancing at a tremendous pace, it is becoming clear that one of the greatest hurdles to successful stem cell-derived therapies is overcoming immune rejection of the transplant. Although the use of immunosuppressive drugs can decrease the incidence of acute graft rejection, the burden of problems associated with prolonged immunosuppression must be reduced. Strategies inducing specific immunological tolerance complemented by enhanced immune function will bring stem cell therapies closer to reality.