Transmissible spongiform encephalopathies, or prion diseases, are lethal neurodegenerative disorders caused by the infectious agent named prion, whose main constituent is an aberrant conformational isoform of the cellular prion protein, PrPC. The mechanisms of prion-associated neurodegeneration and the physiologic function of PrPC are still unclear, although it is now increasingly acknowledged that PrPC plays a role in cell differentiation and survival. PrPC thus exhibits dichotomic attributes, as it can switch from a benign function under normal conditions to the triggering of neuronal death during disease. By reviewing data from models of prion infection and PrP-knockout paradigms, here we discuss the possibility that Ca2+ is the hidden factor behind the multifaceted behavior of PrPC. By featuring in almost all processes of cell signaling, Ca2+ might explain diverse aspects of PrPC pathophysiology, including the recently proposed one in which PrPC acts as a mediator of synaptic degeneration in Alzheimer's disease.