Covalent protein modification chemistries have become an essential component to a wide array of fields ranging from drug discovery and chemical biology to materials chemistry. As a result, the development of new ligation chemistries with enhanced sophistication and new capabilities serve to not only enable access to protein conjugates with new functional properties but can also provide unique lenses through which to probe biological structure and processes directly in a native environment. This seminar will discuss recent efforts by our group to develop unique chemical transformations that covalently modify biological matter via unusual or underexplored mechanistic pathways as well as their application in the study of complex biological systems.