Effective treatment of neurodegenerative disease is one of the major challenges facing biomedical research. These disorders, which include Alzheimer's, Huntington's and Parkinson's diseases - as well as the rarer prion diseases - constitute an ever-increasing burden in the developed world, socially, medically and economically. The key barrier to effective therapy is that they present clinically when neuronal loss is advanced, and irreversible. Current treatments are almost all directed at modifying symptoms; few address underlying pathogenic mechanisms and are inevitably delivered too late to rescue dying neurons. In the field of prion diseases, however, insights into the molecular basis and the temporal evolution of prion neurotoxicity are increasing. Recent work in mice leads to new hope for the treatment of these disorders, and potentially for rescuing neurodegeneration more broadly. Using lentivirally mediated RNA interference (RNAi) against native prion protein (PrP), White et al report the first intervention resulting in neuronal rescue, prevention of symptoms and increased survival in mice with established prion disease. Central to the effectiveness of this strategy are both the target and the timing of the intervention: the treatment prevents the formation of the neurotoxic prion agent at a point when diseased neurons can still be saved from death. This review introduces the basic concepts of prion pathogenesis, emerging insights into mechanisms of prion neurotoxicity and the rationale for targeting endogenous prion protein (PrP) in prion therapeutics. It describes the discovery of a window of reversibility of early neuronal damage in prion disease and how together these advances led to the subsequent development of the strategy using RNAi based therapy for these disorders. It discusses the use and relevance of this approach more broadly in neurodegeneration.