The prion protein (PrP) is involved in causing a group of diverse transmissible, heritable and sporadically occurring neurodegenerative diseases. Although the identity, nature and replication of the transmissible agent have been intensely studied for decades, the cellular events underlying neuronal dysfunction and death have received comparatively little attention. Recent studies examining the occurrence and consequences of inappropriate cytoplasmic expression of the normally cell-surface PrP underscore an emerging role for PrP trafficking in prion disease pathogenesis.