Numerous transmembrane and glycosylphosphatidylinositol (GPI)-anchored proteins, covering a vast range of structural and functional classes, are recognized to undergo proteolytic cleavage or shedding from the plasma membrane. Although this widespread phenomenon seems fundamental to normal cellular biology, proteolytic processing also seems to play a central role in the pathogenesis of some neurodegenerative disorders such as Alzheimer's disease. An analogous situation may exist in prion disorders. The GPI-anchored cellular prion protein (PrP^C) may be endoproteolytically cleaved at two different sites: one at the C-terminal end of the octameric repeat region and the other within a potentially neurotoxic and amyloidogenic region of the protein. The relevance of these alternative proteolytic events to normal cell function and pathogenesis is incompletely resolved. Study and characterization of the constitutive processing of PrP^C will provide insight into the biological relevance of alternative cleavages in terms of normal PrP^C function, and also into the potential role, if any, to disease causation.