Over the past 40 years, the search for new antibiotics has been Largely restricted to well-known compound classes active against a standard set of drug targets. Although many effective compounds have been discovered, insufficient chemical variability has been generated to prevent a serious escalation in clinical resistance. Recent advances in genomics have provided an opportunity to expand the range of potential drug targets and have facilitated a fundamental shift from direct antimicrobial screening programs toward rational target-based strategies. The application of genome-based technologies such as expression profiling and proteomics will Lead to further changes in the drug discovery paradigm by combining the strengths and advantages of both screening strategies in a single program.