The presence of the cellular prion protein (PrPC ) on the cell surface is critical for the neurotoxicity of prions. Although several biological activities have been attributed to PrPC , a definitive demonstration of its physiological function remains elusive. In this review, we discuss some of the proposed functions of PrPC , focusing on recently suggested roles in cell adhesion, regulation of ionic currents at the cell membrane and neuroprotection. We also discuss recent evidence supporting the idea that PrPC may function as a receptor for soluble oligomers of the amyloid β peptide and possibly other toxic protein aggregates. These data suggest surprising new connections between the physiological function of PrPC and its role in neurodegenerative diseases beyond those caused by prions.