Dysregulated cell death in several tissues is intimately involved in the pathogenesis of sepsis and contributes to multiple organ failure. Whether cell death during sepsis occurs by necrosis or apoptosis may depend on the cell type as well as the disease stage and is therefore a matter of intense debate. While lymphocyte apoptosis contributes to immunosuppression in sepsis, recent evidence suggests that necrosis of hepatocytes predominates in septic patients with liver dysfunction and correlates with poor survival. These distinct modes of cell death might have different consequences for the inflammatory response but are also critical for therapeutic interventions and the disease outcome. Understanding the complexity of death processes employing recently available serum biomarkers of cell death could lead to novel therapeutic approaches and assist in the steering of sepsis treatment.