Prion diseases (PrDs) are a group of uniformly fatal neurodegenerative diseases that affect humans and other mammals. At a molecular level, all PrDs are caused by the misfolding of the normal prion protein (PrPC, in which C stands for the normal cellular form) into an abnormal, misfolded form called the prion or PrPSc (in which Sc stands for the scrapie, the prion disease of sheep and goats). Progressive misfolding of prion proteins and spread of prions in the brain lead to unique pattern of neurodegeneration (1). Clinically, the molecular and neuropathological changes lead to protean neurobehavioral manifestations in humans (2, 3). Most cases of human prion disease (hPrD) develop sporadically and are called sporadic Creutzfeldt-Jakob disease (sCJD), but there are also genetic (often familial) forms, and very rarely acquired forms (aCJD) from iatrogenic (i.e., iCJD) or environmental exposure to tissues infected with prions (1). The main objective of this chapter is to provide a clinical description of these three forms of hPrD.