Prions are unprecedented infectious pathogens that cause a group of invariably fatal, neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). The human prion disease Creutzfeldt-Jakob disease (CJD) generally presents as a progressive dementia, whereas scrapie of sheep and bovine spongiform encephalopathy (BSE) are manifest as ataxic illnesses. Prions are devoid of nucleic acid and seem to be composed exclusively of a modified isoform of PrP designated PrP^Sc. The normal, cellular PrP designated PrP^C is converted into PrP^Sc through a process whereby some of its α-helical structure is converted into β-sheet. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens with a nucleic acid genome, prions encipher strain-specific properties in the tertiary structure of PrP^Sc. Transgenetic studies argue that PrP^Sc acts as a template upon which PrP^C is refolded into a nascent PrP^Sc molecule through a process facilitated by another protein.