Cross-coupling reactions are another class of metal catalysis that has been one of the main focuses in the protein modification field (Scheme 8A, 8B). As various palladium cross-coupling methods emerged in the realm of synthetic organic chemistry during the past decades, the bioconjugation field has also been extensively examining their capabilities and utilities. The fundamental catalytic actions and reaction mechanisms of such cross-coupling bioconjugation approaches follows the same principle as that of the small molecule chemistry (e.g., oxidative addition, transmetallation, and reductive elimination). Often, electrophilic nature of a metal center after oxidative addition has been leveraged for both catalytic and noncatalytic protein bioconjugation strategies. A tyrosine-selective palladiumcatalyzed approach (Tsuji-Trost coupling) is one of the earliest examples among the palladium-based methods, driven by deprotonation of the phenol group making it a favorable nucleophile at high pH over other amino acid side chains. Another catalysis example is active-site cysteine selective through coordination of an auxiliary ligand to the palladium center. Other metal sources can be utilized for cross-coupling reactions of proteins including copper catalysis with use of boronate compounds as transmetallation reagents that modifies the amide backbone N-H group (Chan-Lam coupling). The original report by Ball and co-workers made use of a copper binding motif with a histidine residue-that is akin to known metalbinding peptide sequence called amino terminal copper and nickel (ATCUN) motif-to activate the backbone N-H and to facilitate the reductive elimination between the amide and boronate-derived group. Recently, use of a different solvent and different amino acid binding patterns 134 have been shown to achieve similar chemistry without aids of the histidine residues as well. Gold would be another metal source that allows for crosscoupling reactions on proteins targeting a tryptophan residue in aqueous acetonitrile solution. While this specific gold chemistry is the sole example of cross-coupling-based gold catalysis, several non-catalytic Au bioconjugation approaches have been reported to date, and together with its relatively lower toxicity compared to other transition metals, 138,139 development of gold catalysis may be merely in a nascent state for potential growth.