The emergence and increasing occurrence of bacterial strains that are resistant to all classes of available antibiotics is a global problem. Current antimicrobials target a relatively small number of essential gene functions including: inhibition of cell wall biosynthesis, and synthesis of macromolecules (proteins, DNA and RNA). Treatment of infections caused by antibiotic resistant bacteria requires new approaches and agents with novel modes of action. The bacterial extracellular proteome (cell envelope, membrane vesicles and secreted proteins) plays a fundamental role in establishing infection by enabling the microbes to adhere to and invade host cells, facilitating nutrient acquisition, host tissue destruction, and suppression of host immune responses. Hence the components of the extracellular proteome are promising targets for drugs/vaccines aimed at preventing bacterial infections. The long-term goal of our research is to enhance our understanding of the phenotypic plasticity of the bacterial extracellular proteome and utilize this information to identify attractive targets for the development of new therapeutic interventions. Currently, our research focuses on the role of bacterial extracellular proteomes in colonization and circumvention or exploitation of host immune response using a model organism, Neisseria gonorrhoeae. We examine these issues using comprehensive proteomic studies (iTRAQ, TMT), chemical genomics, metabolomics, and state of the art genetic, molecular and biochemical methods.