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The discovery of the structure of DNA and the elucidation of the molecular mechanisms of replication, transcription, and translation are the foundations of modern biology and medicine. However, in the early 80s, the prion hypothesis introduced a new system of biological information transfer that does not rely on DNA; it introduced the concept of conformational propagation through templating. Unlike the molecular biology revolution, which was based on detailed molecular structures and mechanisms, the prion hypothesis was postulated in the absence of clear molecular structures or mechanisms. In this perspective, we highlight nine points in which the prion hypothesis contradicts the molecular, structural, and mechanistic experimental evidence accrued since its inception four decades ago. Alternatively, we postulate that an extension of the thermodynamic hypothesis of protein folding (Anfinsen’s dogma) to the state of proteins at high concentration (supersaturation) is better suited for explaining the different facets and pathways of protein aggregation.