Sepsis was recently redefined as a “a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated host immune response to infection.” This sunrise seminar, presented by an intensivist-immunologist, will explore the immune response during acute infection, with a focus on what “dysregulated” actually means. Novel approaches for classifying septic patients based on immunologic endotype will be reviewed, and recent therapeutic strategies specifically targeting the dysregulated immune response will be considered.