In the past decade, the interaction between prions and nucleic acids has garnered significant attention from the scientific community. for many years, the participation of RNA and/or DNA in prion pathology has been largely ruled out by the "protein-only" hypothesis, but this is now being reconsidered. Experimental data now indicate that nucleic acids (particularly RNA), besides being carriers of genetic information, function as important key components during development, physiological responsiveness and cellular signaling. This revelation has brought a new perspective to prion pathology. Here we discuss the role of RNA molecules in prion protein aggregation and the resulting cellular toxicity. We combine our most recent findings with existing literature to shed new light on this exciting field of research.