The ability to selectively perform chemical reactions within living systems has transformed the field of Chemical Biology. These chemoselective processes have had a major scientific impact by enabling studies of cellular processes, producing tools for the ligations of large biomolecules, and advancing our ability to image or track small molecular changes such as posttranslational modifications. As more investigators become involved in the development and application of chemical reactions performed within complex biological settings, there have been a rising number of innovations that create improved tools and resources for understanding nature. This perspective highlights some recent achievements that show how innovation and creativity can provide new opportunities in this exciting and rapidly expanding area of chemical research.