Prion protein (PrP) is probably the only known protein that possesses chameleon-like features, as reflected not only in its conformation but also in its function. Cellular PrP (PrP^C), rich in α-helical structures, is believed to be functionally involved in neurotransmitter metabolism, immune cell activation, cell adhesion, signal transduction, copper metabolism, antioxidant activity, and programmed cell death. Its pathologic conformer (PrP^Sc), rich in β-sheet structures, plays an essential role in the pathogenesis of prion diseases, a group of age-related transmissible neurodegenerative disorders which, as in Alzheimer’s disease, inevitably attack human cognition. Histologically, PrP is highly concentrated in the central nervous system although it is also widely expressed in the peripheral tissues and organs at lower levels. Observations indicating that a pronounced cognitive deficit is often evident in the early stage of prion diseases strongly imply that PrP is associated with human cognition. Indeed, cognitive deficit is one of a few phenotypes identified in mice lacking PrP. This article highlights evidence of the involvement of PrP^C in human cognition. In addition, it puts forth the hypothesis that the novel conformer of an insoluble PrP identified in the normal brain constitutes a molecule associated with long-term memory and that two potential PrP-implicated pathways are operative in human cognition.