ABSTRACT: Although much is known about prion diseases (characterized by a post-translational misfolding of the prion protein [PrP]) and their neuropathology and molecular pathology, the fundamental cause of illness, the basic neuropathogenesis, remains uncertain. There are three broad considerations discussed in this review: the possible loss of normal PrP function, the possible direct toxicity of the abnormally folded PrP and a harmful interaction between the normal and abnormal protein. In considering these possibilities, there are difficulties, including the facts that the relevant normal functions of the PrP are somewhat uncertain and that there are a number of possible toxic species of abnormal protein. In addition to the possible interactions of normal and abnormal PrP in prion disease, PrP may play a role in the neuropathogenesis of other diseases (such as Alzheimer’s disease).