Prion diseases display multiple disease phenotypes characterized by diverse clinical symptoms, different brain regions affected by the disease, distinct cell tropism and diverse PrP^Sc deposition patterns. The diversity of disease phenotypes within the same host is attributed to the ability of PrP^C to acquire multiple, alternative, conformationally distinct, self-replicating PrP^Sc states referred to as prion strains or subtypes. Structural diversity of PrP^Sc strains has been well documented, yet the question of how different PrP^Sc structures elicit multiple disease phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that carbohydrates in the form of sialylated N-linked glycans, which are a constitutive part of PrP^Sc, are important players in defining strain-specific structures and disease phenotypes. This article introduces a new hypothesis, according to which individual strain-specific PrP^Sc structures govern selection of PrP^C sialoglycoforms that form strain-specific patterns of carbohydrate epitopes on PrP^Sc surface and contribute to defining the disease phenotype and outcomes.