Severe infection and the patient response constitute sepsis. Here, we review the meta-genome (patient genetics, pathogen communities and host response) and its impact upon the outcome of severe sepsis. Patient genetics, both predisposition for infection and the subsequent response to infection are reviewed. The pathogen is discussed with particular emphasis upon the modern era of microbiome analysis and nucleic acid diagnostics. Finally, we discuss the host clinical and immune responses and present new data to suggest that the immune response is the key to understanding sepsis and improving a death rate of nearly 30%.