It is generally accepted that the functional activity of biological macromolecules requires tightly packed three-dimensional structures. Recent theoretical and experimental evidence indicates, however, the importance of molecular flexibility for the proper functioning of some proteins. We examine high-resolution structures of proteins in various functional categories with respect to the propagation of the secondary structure. The latter was considered as a characteristic of the inherent flexibility of a polypeptide chain. We found that the proteins in functionally competent conformational states might be comprised of 20 to 70% flexible residues. For instance, proteins involved in gene regulation, e.g., transcription factors, are, on average, largely disordered molecules with over 60% of amino acids residing in ‘coiled’ configurations. In contrast, oxygen transporters constitute a class of relatively rigid molecules with only 30% of residues being locally flexible. Phylogenic comparison of a large number of protein families with respect to the propagation of secondary structure illuminates the growing role of the local flexibility in organisms of greater complexity. Furthermore, the local flexibility in protein molecules appears to be dependent on the molecular confinement, and is essentially larger in extra-cellular proteins.