Cellular prion protein (PrP C ) has been well described as an essential partner of prion diseases due to the existence of a pathological conformation (PrP Sc ). Recently, it has also been demonstrated that PrP C is an important element of the pluripotency and self-renewal matrix, with an increasing amount of evidence pointing in this direction. Here, we review the data that demonstrate its role in the transcriptional regulation of pluripotency, in the differentiation of stem cells into different lineages (e.g. muscle and neurons), in embryonic development, and its involvement in reproductive cells. Also highlighted are recent results from our laboratory that describe an important regulation by PrP C of the major pluripotency gene Nanog. Together, these data support the appearance of new strategies to control stemness, which could represent an important advance in the field of regenerative medicine.Reproduction (2013) 146 R91-R99