Sepsis is currently defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and is estimated globally to be responsible for 11 million deaths each year. Despite the therapeutic potential of immunomodulatory therapy, there have been very few successful trials of such agents in patients with this clinical syndrome. I will describe recent efforts to better understand the pathophysiology of sepsis and stratify the maladaptive host response into sub phenotypes associated with specific mechanisms, showing how this can reveal potential targets and biomarkers to guide their therapeutic use.