As chemical biologists sought methods to modify and study biomolecules in their native environments, the need for bioorthogonal chemical reactions emerged. These fast and selective reactions between otherwise inert, abiotic functional groups have enabled exploration of some of the most intriguing and challenging questions in chemical biology. Further, the ability to perform organic reactions in cells and organisms has led to important applications in clinical spaces, and one reaction is now an integral part of a phase 2 trial for treating solid tumors. Given that bioorthogonal chemistry was a recipient of the 2022 Nobel Prize, we expect this field to be even more energized. Here, we highlight some of the most recent studies in this sphere and how these set the stage for where bioorthogonal chemistry is headed.