Abstract Microbes have evolved a myriad of mechanisms to overcome the toxic effects of antibiotics, which include the production of enzymes that modify or degrade antibiotics, complex membrane‐associated efflux systems that can pump antibiotics out of the cell, modification of antibiotic targets, and the production of immunity proteins. The biochemical logic of resistance is often intimately linked with the mode of action of the antibiotics. As a result, chemical biology approaches for understanding resistance not only have application in our understanding of this phenomenon, but also they can guide the generation and deployment of new antibiotics. In this review, a survey of the chemical strategies employed by bacteria to resist antibiotics is presented with an emphasis on the molecular mechanisms of resistance enzymes and proteins.