Prion diseases are a group of fatal neurodegenerative disorders affecting both humans and animals. They are the only known diseases that exist in three etiologically different forms as sporadic, inherited, and acquired conditions. The possible causal link between two disease subtypes, bovine spongiform encephalopathy (mad cow disease) in cattle and a new variant of Creutzfeldt-Jakob disease in humans, has highlighted the need for a thorough understanding of the disease pathogenesis. Considerable evidence has accumulated in support of the prion hypothesis which states that the diseases are due to altered form of prion protein capable of self-replication and transmission. This review summarizes the current knowledge of prion diseases in terms of pathological phenotypes, molecular features of prion protein, and putative mechanisms of pathogenesis.