Fatal familial insomnia (FFI) is linked to a mutation at codon 178 of the prion protein gene, coupled with the methionine codon at position 129, the site of a methionine/valine polymorphism. The D178N mutation coupled with the 129 valine codon is linked to a subtype of Creutzfeldt-Jakob disease (CJD178) with a different phenotype. Two protease resistant fragments of the pathogenic PrP (PrP(res)), which differ in molecular mass, are associated with FFI and CJD178, respectively, suggesting that the two PrP(res) have different conformations and hence they produce different disease phenotypes. FFI transmission experiments, which show that the endogenous PrP(res) recovered in affected syngenic mice specifically replicates the molecular mass of the FFI PrP(res) inoculated and is associated with a phenotype distinct from that of the CJD178 inoculated mice, support this idea. The second distinctive feature of the FFI PrP(res) is the underrepresentation of the unglycosylated PrP(res) form. Cell models indicate that the underrepresentation of this PrP(res) form results from the PrP dysmetabolism caused by the D178N mutation and not from the preferential conversion of the glycosylated forms. Codon 129 on the normal allele further modifies the FFI phenotype determining patient subpopulations of 129 homozygotes and heterozygotes: disease duration is generally shorter, insomnia more severe and histopathology more restricted to the thalamus in the homozygotes than in the heterozygotes. The allelic origin of PrP(res) fails to explain this finding since in both cases FFI PrP(res) is expressed only by the mutant allele. Despite remarkable advances, many issues remain unsolved precluding full understanding of the FFI pathogenesis.