Perhaps the most unorthodox feature of prion disease is the co-existence of infectious, genetic and sporadic forms of this class of neurodegenerative diseases. With the recent occurrence of new variant Crretzfeldt-Jakob disease in the United Kingdom and the link to Mad Cow disease, it is important to understand the molecular basis of this class of diseases and begin to develop therapeutic agents. The tools of structure based drug design will be used to identify plausible inhibitors of key step(s) in prion replication from an analysis of the structure of PrPc. Preliminary work has identified a collection of leads studied for their ability to terminate multi-merization mediated by intermolecular beta- structure. Finally, peptides that are capable of inducing prion neuropathology in a conformation dependent fashion will be studied to better understand the molecular requirements for prion activity. These efforts should yield improved assays for inhibitors of prion replication. A close collaboration between biologists, synthetic chemists, computational biophysicists and biochemists, computational biophysicists and biochemists is proposed to achieve these goals. Success in the development of therapeutic strategies should have implications for the treatment of other neurodegenerative diseases that involve protein aggregation.