As age progresses, the regenerative power of one's own pluripotent stem cells is often inadequate to sustain normal tissue function. Consequently, the incidence of chronic and degenerative diseases has significantly increased. The derivation of adult tissues and organs from a variety of stem cell sources represents the starting mark for regenerative medicine. It is currently considered a developing mean to repair, restore, maintain, or enhance organ functioning through life span. Recent advances in human embryonic stem cells (hESC) research, however, made the prospect of cell replacement therapy even more compelling and highlighted hESC as a fast track in the therapeutic hope. Among the hurdles which have been largely overlooked in the excitement over the expected benefit is the immunogenicity. Indeed, beyond the clear need to establish the safety of hESC and their derived tissues in terms of tumorogenicity and potential to transmit infections, the challenge is to overcome the immunological barriers to their transplantation.