Elucidation of the structure of PrPSc continues to be one major challenge in prion research. Molecular basis of the biology of prion protein, such as the molecular mechanism of prion replication and aggregation, the species barrier and the pathogenesis of neurodegeneration will not be understood until the structure is solved. Given that high-resolution techniques such as NMR or X-ray crystallography cannot be used, a number of lower resolution analytical approaches have been attempted.