The cellular prion protein, PrPC, has been extensively investigated for its role in prion diseases, a class of neurodegenerative disorders caused by the structural conversion into PrPSc. Several studies using PrP knock-out models do not reveal marked phenotypes; nevertheless, the protein localization in the extracellular side of the plasma membrane may suggest that PrPC can exert a plethora of different functions. PrPC interaction with many intracellular and extracellular partners makes most of these functions quite confounding, including its role as a putative receptor/acceptor for other β-sheets-enriched amyloid proteins. In fact, PrPC has been reported to interact with aggregated forms of amyloid β peptide, tau and α-synuclein, which characterize many neurodegenerative disorders. For most of these aggregates, the interaction with PrPC seems responsible to mediate, at least in part, most of the detrimental outcome observed in these pathologies. These results indicate PrPC as an important mediator of amyloid toxicity and suggest the need for further studies to delineate whether its targeting may represent a valid strategy to counteract neurodegenerative diseases.