Resistance to existing antibiotics has emerged as a major problem in healthcare. Novel antibiotics for which bacteria have not yet acquired resistance need to be developed to combat drug-resistant pathogens. Aminoacyl-tRNA synthetases are leading targets for novel anti-infectives. The validation of aminoacyl-tRNA synthetases as drug targets for anti-infectives has been established in an animal system. Using several conceptually distinct approaches, new inhibitors of synthetases have been developed as drug prototypes.