We are currently entering a challenging new era where microbial resistance to antibiotics will complicate the treatment of nearly all common bacterial infections. The ability to develop new antimicrobials has lagged behind the development of resistance for many life-threatening bacterial species. Novel ways to combat infection and discover new antibiotics will be paramount to winning the war against microbial resistance. We are currently working to develop in vivo models of infection in hosts such as zebrafish (Danio rerio) that are well suited for systematic, high-throughput in vivo study of the host-pathogen relationship. Genes which have been identified as critical to in vivo pathogenesis would define a new class of anti-microbial targets based on virulence while identification of candidate small molecules and their protein targets will reveal novel therapeutic leads.