The mobility of cellular prion protein (PrP) in specific cell membrane domains and among distinct cell compartments dictates its molecular interactions and directs its cell function. PrP works in concert with several partners to organize signaling platforms implicated in various cellular processes. The scaffold property of PrP is able to gather a molecular repertoire to create heterogeneous membrane domains that favor endocytic events. Dynamic trafficking of PrP through multiple pathways, in a well-orchestrated mechanism of intra and extracellular vesicular transport, defines its functional plasticity, and also assists the conversion and spreading of its infectious isoform associated with neurodegenerative diseases. In this review, we highlight how PrP traffics across intra- and extracellular compartments and the consequences of this dynamic transport in governing cell functions and contributing to prion disease pathogenesis.