Cell-based regenerative therapy use of pluripotent stem cells of embryonic origin (ESC) as well as induced pluripotent stem cells (iPS) has emerged as a new alternative for a number of clinical conditions where the functional capacity is severely and irreversibly impaired.In certain conditions, survival of these cells could be achieved in nonimmunosuppressed, immunocompetent recipients. There are, however, a wealth of reports showing that in other xenogeneic or allogeneic situations it has been impossible to obtain the survival of pluripotent cell-derived progenitors in the absence of immunosuppression. Although rejection is well controlled by immunosuppressive treatment, the infectious and tumorigenic risks associated with these drugs justify the search for less aggressive strategies.The only sensible way to circumvent this problem is the induction of immune tolerance. Here we describe the basis for such a strategy, and we discuss recent results supporting its feasibility in terms of clinical translation. © 2014 Elsevier Inc. All rights reserved.