Herein we report a Cu-catalyzed, site-selective functionalization of peptides that employs an aspartic acid (Asp) as a native directing motif, which directs the site of O-arylation at a proximal tyrosine (Tyr) residue. Through a series of competition studies conducted in high-throughput reaction arrays, effective conditions were identified that gave high selectivity for the proximal Tyr in Asp-directed Tyr modification. Good levels of site-selectivity were achieved in the O-arylation at a proximal Tyr residue in a number of cases, including a peptide-small molecule hybrid.