Prion diseases are transmissible, invariably fatal, neurodegenerative diseases which include Creutzfeldt–Jakob disease (CJD) in humans and bovine spongiform encephalopathy and scrapie in animals. A large number of putative treatments have been studied in experimental models over the past 30 years, with at best modest disease-modifying effects. The arrival of variant CJD in the UK in the 1990s has intensified the search for effective therapeutic agents, using an increasing number of animal, cellular and in vitro models with some recent promising proof of principle studies. Here, for the first time, we present a comprehensive systematic, rather than selective, review of published data on experimental approaches to prion therapeutics to provide a scientific resource for informing future therapeutics research, both in laboratory models and in clinical studies.