It is now accepted that a conformational change of the cellular prion protein (PrPC) generates the prion, the infectious agent responsible for lethal neurodegenerative disorders, named transmissible spongiform encephalopathies, or prion diseases. The mechanisms of prion-associated neurodegeneration are still Obscure, as is the cell role of PrPC, although increasing evidence attributes to PrpL important functions in cell survival. Such a behavioral dichotomy thus enables the prion protein to switch from a benign role Under normal conditions, to the execution of neurons during disease. By reviewing data from models of prion disease and PrPC-null paradigms, which suggest a relation between the prion protein and Ca2+ homeostasis, here we discuss the possibility that Ca2+ is the factor behind the enigma of the pathophysiology of PrPC. Ca2+ features in almost all processes of cell signaling, and may thus tell us much about a protein that pivots between health and disease. (C) 2008 Elsevier Inc. All rights reserved.