The Transmissible spongiform encephalopathies (TSEs) form a group of illnesses, characterized by a pathological form of the native prion protein, which results in a rapidly progressive neurodegenerative illness. They also are responsible for Gerstmann-Strâussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI), and they have been produced experimentally in several other animals. Creutzfeldt-Jakob disease (CJD) is the most common TSE in humans. Human prion diseases have three etiologies: (a) sporadic, (b) genetic, and (c) acquired. Human prion diseases are important to understand because of their underlying pathophysiology, public health implications, and clinical features that often result in misdiagnosis. This chapter reviews the historical discovery of prion diseases and the formulation of the prion hypothesis. It explores prion hypothesis and the neuropathogenesis of prion diseases. The chapter ends with a description of the diagnosis, prognosis, and experimental treatment of human prion diseases.