For a globular protein, function follows structure. Under physiological conditions, many proteins undergo a spontaneous disorder ⇌ order transition called folding. The protein polymer is highly flexible when unfolded but adopts its unique native, three-dimensional structure when folded. Current experimental knowledge comes primarily from thermodynamic measurements in solution or the structures of individual molecules, elucidated by either X-ray crystallography or NMR spectroscopy. From the former, we know the enthalpy, entropy and free energy differences between the folded and unfolded forms of hundreds of proteins under a variety of solvent/co-solvent conditions. From the latter, we know the structures of ~80,000 proteins, which are built on scaffolds of α-helix and β-sheet, hydrogen-bonded structural elements proposed by Pauling. In Nobel prize-winning experiments, Anfinsen showed that the amino acid sequence alone is sufficient to determine a protein’s structure; no auxiliary molecular components or addition of energy is needed. Most proteins self-assemble spontaneously in water with a little salt at physiological temperature. The molecular mechanism responsible for this self-assembly process remains an open question – probably the most fundamental open question in biochemistry. Our current mindset tracks back half a century to a hypothesis of Anfinsen: under folding conditions, each protein attains its native state by sliding down a free-energy gradient to the global minimum. In contrast to this time-honored view, we propose an alternative viewpoint in which the folded state is selected from a limited repertoire of structural possibilities, each corresponding to a distinct hydrogen-bonded arrangement of α‑helices and/or strands of β‑sheet.