Prion diseases represent a distinctive class of rare, rapidly progressing, and invariably fatal neurodegenerative diseases that exert their devastating effects within the central and peripheral nervous systems. Prion diseases stem partly from the perturbation of the native prion protein, cellular prion protein (PrPC), resulting in the emergence of a pathogenic isoform, and scrapie prion protein (PrPSc). Prion diseases encompass a spectrum including environmental induction, heredity/genetics, and exposure to infective prions. Prion diseases have neuropathological hallmark markers. Pathologies include spongiform encephalopathy, neuronal destruction, gliosis, and the accumulation of conglomerates of prion protein in diverse forms, interwoven with obdurate neurofibrillary structures. Prion diseases have eluded curative interventions, resulting in morbidity and mortality. This chapter reports on the confrontation of biomedical sciences with prion diseases and includes prion disease pathophysiology, complex cellular and molecular characteristics, recent progress that illustrates the physiological role of various prion proteins, the variations of various prions, their dysfunction, neurotoxicity, sophisticated mechanisms of prion propagation, and prion disease progression.