The genetic code, elucidated in the 1960s through the work of Nirenberg, Ochoa, and Khorana, provides a set of molecular instructions for turning DNA into proteins. What if we could change the meaning of those instructions and decide for ourselves how to interpret the genetic code? Over the last decade, cells have been outfitted with modified molecular machinery that enables them to use non-standard sets of amino acids to make proteins. These developments are leading to new approaches to macromolecular design, protein evolution, biological imaging, and proteome-wide analysis of cellular processes.