Enzymes perform complex and selective chemistry on all scales, assembling the molecules of life in every organism and synthesizing important small-molecule drugs in industrial reactors. Ideally we would conduct most organic chemistry enzymatically, forging new direct routes to synthetic targets, increasing selectivity and yield for our most challenging transformations, and minimizing chemical waste. But we are only scratching the surface—protein sequence space is vast and we explore it at a glacial pace, limited by low-throughput analytical chemistry (like liquid chromatography–mass spectrometry). We seek to understand how nature catalyzes its most selective chemistry and how we can use those principles to unlock new enzymatic reactions in the flask. We build small-molecule biosensing circuits in E. coli to detect small-molecule ligands in high throughput, enabling continuous directed evolution of proteins that bind and transform small molecules.