Prion diseases, or transmissible spongiform encephalopathies (TSEs), are mammalian neurodegenerative diseases that occur as sporadic, inherited, or iatrogenic forms. Human TSEs exhibit a wide spectrum of phenotypic variability, which is influenced by (1) the conformation of the pathologic prion protein, or PrP(Sc); (2) the polymorphic codon 129 of the prion protein gene (PRNP), involving synonymous or nonsynonymous expression of Met or Val; and (3) the site of formation or entry of the self-replicating PrP(Sc). Brain deposition of PrP(Sc) occurs in a phenotype-specific regional pattern, either as extracellular amyloid plaques and plaque-like aggregates, or as fine granular immunoreactivity at intracellular sites and presynaptic and postsynaptic locations, including dendrites. We previously demonstrated PrP(Sc) deposition in ciliated dendrites of olfactory sensory neurons in sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease. PrP(Sc) immunoreactivity was not limited to the olfactory neuroepithelium. But additionally involved the central olfactory pathway. More recently, we have found that the pathology of the olfactory pathway occurs early in the disease course, either in the myoclonic or classic sCJD or in the ataxic variant. Intriguingly, in the ataxic or cerebellar variant, mainly observed in patients with the Met/Val polymorphism (2) carrying PrP(Sc) type 2, olfactory involvement is accompanied by pathologic changes in the dorsal motor nucleus of the vagus and other brainstem nuclei. These findings suggest that different molecular events and distinct routes of PrP(Sc) spread contribute to the prominent heterogeneity of sCJD, conceivably providing support to the olfactory pathogenesis theory of neurodegenerative diseases.