The key event in prion diseases seems to be the conversion of the prion protein PrP from its normal cellular isoform (PrP(C)) to an aberrant "scrapie" isoform (PrP(Sc)). Earlier studies have detected no covalent modification in the scrapie isoform and have concluded that the PrP(C) --> PrP(Sc) conversion is a purely conformational transition involving no chemical reactions. However, a reexamination of the available biochemical data suggests that the PrP(C) --> PrP(Sc) conversion also involves a covalent reaction of the (sole) intramolecular disulfide bond of PrP(C). Specifically, the data are consistent with the hypothesis that infectious prions are composed of PrP(Sc) polymers linked by intermolecular disulfide bonds. Thus, the PrP(C) --> PrP(Sc) conversion may involve not only a conformational transition but also a thiol/disulfide exchange reaction between the terminal thiolate of such a PrP(Sc) polymer and the disulfide bond of a PrP(C) monomer. This hypothesis seems to account for several unusual features of prion diseases.