A review with 35 refs. Creating functional biol. mols. de novo requires a detailed understanding of the intimate relationship between primary sequence, folding mechanism, and packing topol., and remains up to now a most challenging goal in protein design and mimicry. As a consequence, the use of well-defined robust macromols. as scaffolds for the introduction of function by grafting surface residues has become a major objective in protein engineering and de novo design. In this article, the concept of scaffolds is demonstrated on some selected examples, illustrating that novel types of functional mols. can be generated. Re-engineered proteins and, most notably, de novo designed peptide scaffolds exhibiting mol. function, are ideal tools for structure-function studies and as leads in drug design. [on SciFinder (R)]