As with all living organisms, humans are continually exposed to a broad range of bacteria. A variety of host defense mechanisms control the commensal microbiota and, under physiological conditions, prevent invasion of pathogens. However, pathogenic bacteria evolved the ability to avoid or circumvent these mechanisms to invade the host and evoke tissue damage and inflammation. Dysregulated or non-resolving inflammation is a central pathological process underlying diverse disease states. Traditionally, therapeutic approaches have sought to eradicate bacteria directly using antibiotics, with mixed success. This chapter describes diverse strategies that bacterial microbiota, pathobionts, and pathogens use to interact or interfere with host defense mechanisms, in particular those that come into play during the resolution phase of inflammation. In addition, it discusses novel opportunities to pharmacologically manipulate these processes, challenges for translational research, and strategies that might represent complementary therapeutic approaches to conventional management of infections with antibiotics.