To track biochemical goings-on in living things, researchers frequently turn to bioorthogonal chemistry. These reactions attach probes to compounds of interest without disturbing natural reactions. Because biology is diverse, discovering more such reactions is a priority. Now, chemists have adapted phage display to identify promising candidates (ACS Chem. Biol. 2014, DOI: 10.1021/cb500443x). Qing Lin sought to streamline the discovery process by optimizing bioorthogonal chemistry directly in a biological system. He reasoned that a reaction conducted in a peptide microenvironment might be both rapid and specific, desirable traits for bioorthogonal chemistry, if the peptide makes just the right noncovalent interactions with the reaction partners. He and his colleagues at the University at Buffalo, SUNY, tried phage display, a method that uses a natural-selection-like process to choose a peptide from a large library. The team identified a specific peptide sequence that speeds up a palladium-mediated bioorthogonal cross-coupling (shown above). Neal Devaraj, who develops bioorthogonal chemistry at the University of California, San Diego, calls the phage display strategy clever and thought provoking. He’d like to see future studies optimize reactions that don’t require a metal catalyst.