Creutzfeldt-Jakob disease (CJD) is the most prevalent of the human prion diseases, a group of fatal neurodegenerative disorders afflicting both humans and animals. The unique characteristic of these diseases, whether sporadic, dominantly inherited, or acquired by transmission, is the accumulation in the brain of an abnormal isoform (PrPSc) of the cellular prion protein (PrPc). Progress has been made in understanding inherited prion diseases by genetically linking clusters of familial CJD (fCJD) to mutations of the PrP gene (PRNP). One of the largest clusters of fCJD exists among Jews of Libyan origin. The clinical and pathologic manifestations of CJD in this community resemble those seen with sporadic CJD (sCJD), but the incidence is about 100 times higher than in the general population. Initially, this high incidence was attributed to infection via consumption of sheep brains or eyeballs, but a mutation at codon 200 in PRNP resulting in the substitution of lysine (K) for glutamate (E), designated E200K, was identified in this population. The onset of fCJD (E200K) is age dependent and shows nearly complete penetrance by age 85 years. fCJD in Libyan Jews is invariably associated with accumulation of the pathologic isoform PrPSc in the central nervous system. Using mutation-specific antibodies, it was shown that most PrPSc in the brain of these patients originated from the mutant protein. Some studies suggest that mutant PrP may accumulate in brain and other organs due to an impaired degradation, and its accumulation has been postulated to promote conversion into PrPSc. fCJD (E200K) has been transmitted to primates and transgenic mice, highlighting the need to address ethical and public health issues surrounding the possibility of human to human transmission.