It’s commonly accepted that protein folding/misfolding are alternative reactions of unfolded proteins but the principles governing this remain unknown. Here, researchers describe a general concept that links protein folding and misfolding: protein folding and amyloid formation are separated by the supersaturation barrier of a denatured protein. Breakdown of this supersaturation barrier is required to shift the protein to the amyloid pathway, linking Anfinsen’s intramolecular folding universe with the ‘outer’ intermolecular misfolding universe.