Several models for the transmission and progression of prion diseases have arisen, evolving with the acquisition of new experimental results. It is generally accepted that the PrP(Sc) protein is at least part of the infectious particle and the major protein component of the scrapie-associated fibrils (SAFs) that characterize the disease. An additional, unknown cofactor is most likely involved in transmission of the disease, perhaps by influencing the PrP(c) --> PrP(Sc) transition. This review relates experimental observations on the interactions of nucleic acids (NAs) and PrP with specific focus on alterations in structure. In particular, NAs appear to induce PrP(c) to acquire some of the structural and biochemical characteristics of PrP(Sc). An updated hypothesis is related wherein NAs, on the basis of their structure, act in the PrP(c) --> PrP(Sc) transformation by serving as catalysts and/or chaperones and not by encoding genetic information.