Protein function, activity, and stability are implicitly controlled by structure, which can dictate enzymatic events, tune and modify substrate specificity, or can be utilized in the development of new biomaterials. Aromatic amino acids play a critical role in protein structure, folding, and functional activity through hydrophobic and electronic interactions. Practical synthetic access to novel aromatic amino acids would expand the potential of designed protein functions, and can be utilized via non-covalent interactions to finely tune structure and activity. Inspired by synthetic organic strategies, we have developed practical reaction chemistries to produce a range of diverse aromatic amino acids on peptides in solution or on solid phase, which have demonstrated unique fluorescence, spectroscopic, and functional properties. In particular, we have developed a copper-mediated cross-coupling methodology to generate thiophenylalanine and related aryl thiol derivatives from commercially available iodophenylalanine and thiolacetic acid in high yield on peptides on solid phase.¹  4-Thiophenylalanine represents an intriguing functional hybrid of tyrosine and cysteine, and with its nucleophilic thiolate (pK_a = 6.4), is readily elaborated to form a variety of alkylated and redox derivatives. This cross-coupling approach was also applied to synthesize 2-thiophenylalanine at the N-terminus of a peptide (pK_a = 5.1), which can be readily exploited as a rapid, practical approach to native chemical ligation at phenylalanine.²  In addition to thiophenylalanine and similar derivatives, we have also developed methods to produce many other aromatic amino acids in synthesized peptides, including 4-pyrrolidyl-phenylalanine, 4-boronic acid-phenylalanine, 3-mercaptotyrosine, 4-trifluoromethylsulfonyl-phenylalanine, and 4-pyridyl(N-oxide)-alanine. Furthermore, the utility of aromatic amino acids to electronically control proline cis-trans isomerism was explored in 57 model peptides. Herein, synthetic methods and applications of these practically accessible and diverse aromatic amino acids are presented.