Sixty years ago,we had a very primitive view of proteins in terms of ellipsoidal models obtained from studies of the hydrodynamic properties of protein solutions.It was possible to advance from this view of a protein as a colloidal particle to a real (macro) molecule when Sanger determined the amino acid sequence of insulin,and Pauling proposed the α and β structures,based on hydrogen bonding within the protein backbone.Following these advances,we focused on the strengths of inter-side chain hydrogen bonds and hydrophobic interactions,and their influence on protein properties.These considerations provided the basis for,first,experimental and,later,theoretical,studies to determine the three-dimensional structures of proteins and their folding pathways.The evolution of these developments will be described and illustrated.The resulting methodology has provided the basis for biotechnological developments,including the interactions between proteins and other large and small molecules,for example,drug design.