Prion diseases are a heterogeneous group of disorders with an invariably fatal disease course. Although various etiologies have been proposed it is apparent that at least a subset of these diseases are of infectious nature. An essential part of the infectious agent, termed the prion, is mainly composed of an abnormal isoform (PrP(Sc)) of a host-encoded normal cellular protein (PrP(C)). The molecular details of the pathophysiology of this group of diseases are unclear but the conversion of PrP(C) to PrP(Sc) plays a fundamental role. In all human prion diseases, PrP(Sc) is deposited in the central nervous system. These disorders include sporadic, genetic and acquired Creutzfeldt-Jakob disease. The molecular classification of human prion diseases is important in order to understand underlying disease mechanisms and for the development of novel therapy protocols. Current classification systems are based on the assessment of clinical presentation, genetic investigations, neuropathological findings and biochemical analysis of PrP(Sc).