The reengineering of protein-ligand (or enzyme-substrate) interfaces using a combination of chemical and genetic methods has become an increasingly common technique to create new tools to manipulate and study biological systems. Many applications of ligand receptor engineering require that the engineered ligand and receptor function independently of endogenous ligands and receptors. Engineered ligands must selectively interact with modified receptors, and modified receptors must effectively discriminate against endogenous ligands. A variety of chemical design strategies have been used to reengineer ligand-receptor interfaces. The advantages and limitations of various strategies, which involve the manipulation of hydrophobic, polar, and charged residues, are compared. New design strategies and potential applications of ligand-receptor engineering are also discussed.