Clostridium difficile caused or contributed to the deaths of 8700 hospitalized patients in the UK during 2007, making it the most significant hospital-acquired pathogen. C. difficile is estimated to cost the US health care system 3 Billion USD/year (no current estimates available for UK) representing a serious economic burden that impacts the overall performance and safety of our hospitals {Dubberke, 2009}. C. difficile persists in hospitals by exploiting an infection cycle that is dependent on humans shedding highly resistant and infectious spores. As a result, C. difficile is endemic in many hospitals and outbreaks are difficult to contain, highlighting the compelling need to understand the spore-mediated infection cycle and the factors that lead to C. difficile transmission between individuals. The proposed research will utilize cutting edge genomic and proteomic technologies in combination with in vitro and murine models to study the biology of C. difficile spores, specifically, the signals and molecular processes that lead to the formation of spores and the molecular interactions between spores and the host during colonization. This work has the potential to lead to novel infection control interventions that interfere with C. difficile spore formation and block host colonization by spores.