Because resistance has developed to mainline antibiotics, including vancomycin, new antibiotics are now being aggressively sought. For this purpose, aminoacyl tRNA synthetases are being pursued as targets for new drugs. These enzymes are universal and are essential for cell viability. The key to their usefulness lies in being able to find drugs that inhibit a pathogen synthetase but not its human cell counterpart. The possibility for species-specific inhibition was originally demonstrated with a natural product and has now been demonstrated with prototypical drugs that are based on the structure of an intermediate of the aminoacylation reaction. Efficacy of a rationally designed inhibitor has been shown in vivo with a pathogen infection established in an animal model. Although many challenges remain, these early results suggest that synthetases will continue to be of major interest for development of new anti-infectives.