The modern era of antibacterial chemotherapy began in the 1930s, and the next four decades saw the discovery of almost all the major classes of antibacterial agents that are currently in use. However, bacterial resistance to many of these drugs is becoming an increasing problem. As such, the discovery of drugs with novel modes of action will be vital to meet the threats created by the emergence of resistance. Success in discovering inhibitors using high-throughput screening of chemical libraries is rare. In this Review we explore the exciting opportunities for antibacterial-drug discovery arising from structure-based drug design.