Studies on the transmission from man to animals of Creutzfeld-Jacob disease (CJD) led Prusiner to identify a proteinaceous infectious particle lacking nucleic acid, which was called prion. The identification of the infectious prion (PrPsc) then led to the discovery of the normal cellular counterpart (PrPc). One of the still enigmatic aspects regarding prion diseases is actually how, where, and when the transformation PrPc/PrPsc is occurring, this being due to the result of a large extent to the fact that so far most studies have been dedicated to the formation and transmission of PrPsc, whereas the understanding of physiologic roles of PrPc are in their infancy. In this review, we hope to identify the most reliable hypotheses for future experiments on PrPc. This is relevant not only for the understanding of PrPc functions but also to unravel the enigmatic nature of PrPc/PrPsc conversion.