Sepsis is an ill-defined syndrome yet is a leading cause of morbidity and mortality worldwide. The most recent consensus defines sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection. However, this definition belies the complexity and breadth of immune mechanisms involved in sepsis, which are characterized by simultaneous hyperinflammation and immune suppression. In this review, we describe the immunopathogenesis of sepsis and highlight some recent pathophysiological findings that have expanded our understanding of sepsis. Sepsis endotypes can be used to divide sepsis patients in different groups with distinct immune profiles and outcomes. We also summarize evidence on the role of the gut microbiome in sepsis immunity. The challenge of the coming years will be to translate our increasing knowledge about the molecular mechanisms underlying sepsis into therapies that improve relevant patient outcomes.