The development of antimicrobials has advanced tremendously over the past century. However, as our production capacity increases, the threat of resistance is ever-present. To combat this resistance, two main avenues of drug discovery are being pursued: identifying new microbial proteins for which to direct drug discovery efforts, and designing innovative drugs that target existing proteins. The advent of structural genomics research has advanced to the point of rapidly discovering novel microbial protein targets. In addition, modern tools of computational biology greatly enhance the speed and reliability of antimicrobial discovery. The various steps of this process are outlined and discussed, including virtual ligand screening, pocket identification, and compound optimization.