Vascular endothelial growth factor (VEGF) is an important signaling molecule for the growth and differentiation of blood and lymphatic vessels and has been implicated in a variety of disease states. Of particular interest is the overproduction of VEGF in many cancers to recruit blood vessels to tumor sites. To prohibit this angiogenesis, current FDA-approved anti-VEGF treatments, including monoclonal antibodies, bind VEGF with high affinity and thus block VEGF-receptor interactions. Likewise, peptide ligands for VEGF might provide a useful alternative treatment or perform other functions for drug delivery or detection. The goal of engineering such a peptide is, therefore, to assure that it binds specifically to its target protein and with high affinity. Toward that end, a multi-step process of screening and evolution was designed to isolate ligands for VEGF from a combinatorial library displayed on the surface of bacterial cells. To increase affinity and specificity, cooperative binding was introduced through the placement of a second peptide library N-terminal to selected VEGF-binding peptides. Final screening of this library resulted in bidentate peptides with improved binding over their single peptide counterpart. The best peptide sequences were identified based on slow dissociation rate and their ability to bind VEGF in the presence of serum. These engineered peptide ligands might be useful alone as therapeutics or in conjunction with other disease-specific agents or drug-delivery mechanisms. Furthermore, the screening method can be extended to a wide variety of other targets to increase ligand affinity, specificity, and functionality.