Prion diseases, such as Creutzfeld-Jakob disease (CJD) in humans, scrapie in sheep and BSE in cattle, are characterized by formation of insoluble aggregates containing a protease-resistant form (PrP-res) of the cellular prion protein (PrP-sen) in the central nervous system. Development of these diseases requires endogenous PrP-sen, which the infectious PrP-res seems able to convert into more PrP-res. Elimination of PrP-sen might therefore represent an effective way of combating PrP-res. On p. 2775, Joëlle Chabry and co-workers reveal that RNAi technology can do just that. They demonstrate that transfection of scrapie-infected neuroblastoma cells with a 21-nucleotide small interfering RNA (siRNA) directed against the Prnp gene (which encodes PrP-sen) efficiently and specifically inhibits PrP-sen synthesis and drastically reduces accumulation of PrP-res. Importantly, the authors demonstrate that the silencing effect is independent of cell type and scrapie strain, and the siRNA does not appear to be cytotoxic. Their findings indicate that RNAi has potential as a therapeutic approach for treatment of prion diseases and perhaps other diseases characterized by accumulation of insoluble protein aggregates, such as Alzheimer's and Huntington's disease.