Prion diseases are transmissible neurodegenerative disorders of humans and animals for which no effective treatment is available. Conformationally altered, proteaseresistant forms of the prion protein (PrP), termed PrPsc, are critical for disease transmissibility and pathogenesis, thus representing a primary target for therapeutic strategies. Different approaches affecting the clearance of PrPsc, inhibiting or preventing its conformation change are currently under investigation. Some compounds antagonize prion propagation in cellular and / or animal models of the disease. These molecules include polyanions, polyene antibiotics, tetrapyrroles, branched polyamines and compounds termed beta-sheet breakers whose direct target its the abnormal conformational change for PrPsc. The suitability of these compounds for therapy is limited, primarily because they cannot cross the blood-brain barrier (BBB) and / or show severe toxicity. A variety of drugs already used for treatment of unrelated human diseases and known to penetrate the BBB have now been screened. The tricyclic derivatives of acridine and phenothiazine inhibit PrPsc formation in scrapie-infected neuroblastoma cells, confirming earlier reports on anti-prion activity of these compounds. In addition, activation of the immune system has been proposed to increase the clearance of PrPsc and reduce the prion infectivity and antibodies can exert antiaggregation activity. We showed that tetracyclines reverse abnormal physicochemical properties and abolish the neurotoxicity of PrP peptides in vitro. These compounds interact with PrPsc from brain tissue of BSE-affected cattle and patients with new-variant Creutzfeldt-Jakob disease (vCJD). Syrian hamsters injected with tetracycline-treated inoculum showed a significant delay in the onset of clinical signs of disease and prolonged survival time. When tetracycline was pre-incubated with a high dilution of the scrapie-infected inoculum, one third of the hamsters did not develop disease. These conformation-based approaches appear to hold the most promise for prion diseases and for the neurodegenerative disorders associated with protein misfolding. Although several classes of compounds offer anti-prion action their use in clinical practice is limited by the fact they have little or no efficacy at the onset of the disease. Thus, the discovery of more efficient drugs must run in parallel with the development of diagnostic tests to identify TSE earlier.