Sepsis is a dysregulated immune response to an infection that leads to organ dysfunction. Knowledge of the pathophysiology of organ failure in sepsis is crucial for optimizing the management and treatment of patients and for the development of potential new therapies. In clinical practice, six major organ systems — the cardiovascular (including the microcirculation), respiratory, renal, neurological, haematological and hepatic systems — can be assessed and monitored, whereas others, such as the gut, are less accessible. Over the past 2 decades, considerable amounts of new data have helped improve our understanding of sepsis pathophysiology, including the regulation of inflammatory pathways and the role played by immune suppression during sepsis. The effects of impaired cellular function, including mitochondrial dysfunction and altered cell death mechanisms, on the development of organ dysfunction are also being unravelled. Insights have been gained into interactions between key organs (such as the kidneys and the gut) and organ–organ crosstalk during sepsis. The important role of the microcirculation in sepsis is increasingly apparent, and new techniques have been developed that make it possible to visualize the microcirculation at the bedside, although these techniques are only research tools at present.