Medicinal chemistry research has been dramatically transformed by biotechnology. Previously, synthetic chemistry and natural products screening dominated drug research, but now molecular biology has become a driving force behind screening and the establishment of macro-molecular targets. Most of the research in biotech companies has been directed to peptide andprotein therapeutics in spite of problems associated with their low bioavailability, rapid metabolism, and lack of oral activity. Because of these limitations, research groups continue to rely upon chemical synthesis of nonpeptide substances for drug discovery, recognizing that small molecules are likely to remain the most viable avenue for the identification and optimization of potential drugs. The challenge is to devise strategies that take advantage of the strengths of biotechnology to define and characterize molecular targets and of medicinal chemistry to develop compounds. A promising approach integrating these disciplines is the fieldof peptide mimetics, a conceptual approach which considers peptides and proteins not as potential therapeutics but rather as leads for the discovery of other classes of compounds. The terms “peptide mimetics” and “peptidomimetics” have been utilized interchangeably to describe compounds discovered through a variety of research strategies. 1 Indeed, even compounds identified by random screening and subsequently optimizedthrough structural modifi-cation have been termed peptidomimetics if the initial lead was found in an assay in which the natural ligand is a peptide or protein. 2 The field of enzyme inhibitors uses peptide mimetics terminology for replacements of seg-ments of peptide-based substrates and inhibitors. In this Perspective, the emphasis will be on mimetics of peptide and protein ligands for receptors, although the method-