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Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders of humans and animals caused by conformational conversion of a normal host glycoprotein (PrPC) into an infectious isoform (PrPSc). Whereas the mechanism of PrPSc formation and its infectivity are the subject of intensive research, the exact physiological function of PrPC and the mechanism of neurotoxicity are still unknown. Since prion infections are not limited to a monofunctional event, the PrPC/PrPSc conversion, this review will focus on recent insights into the biology of the prion protein uncovered by proteomic approaches. Recent neuroproteomic studies on the protein profile modifications associated with chronic prion infection in cell systems depicted the co-occurring biochemical abnormalities which are the basis of the prion-induced neuronal death and comprise targets for curative drugs. The involvement of other pathways in prion infectivity opens new insights into understanding of the mechanism of cellular toxicity at the molecular level. This can provide further perspectives for identification of novel therapeutic targets and also allows an integrated paradigm in the prion conversion/toxicity biology.