Despite numerous advances in intensive care medicine, sepsis remains a deadly disease. Today, conventional therapeutic approaches and mainstream scientific research mostly focus on symptomatic early goal directed organ support therapy. This includes fluid resuscitation, choice and timing of antibiotics and vasopressors, mechanical ventilation, and renal replacement strategies. Furthermore, great effort has been undertaken to investigate whether tightly controlled blood glucose levels, the application of corticosteroids, and early medication using activated protein C improves survival. However, most of these mainstream approaches have recently been shown unsuccessful in large-scale clinical trials. Current data now suggest that besides giving fluids, antibiotics, and symptomatic organ support, little - if at all - can be done to improve mortality from sepsis. This might be due to the fact that in the presence of modern intensive care medicine, most patients with severe sepsis or septic shock will survive the early "shock phase" of the disease. Mounting evidence suggests that in the course of the disease, most septic patients are then subjected to a secondary phase, which is characterised by a failure of cell-mediated immunity. This leads to repeated and uncontrolled infections, "chronic" multiple organ failure, and death in a large number of cases. Here we hypotheses that in order to profoundly influence survival from sepsis, future therapeutic efforts in the field should concentrate on this later "hypo-immune" stage of sepsis, associated immune phenomena, and novel immunomodulatory strategies. This may lead to the development of advanced immunomodulatory therapies available for widespread clinical use. Today, in the era of antibiotics and advanced organ system support therapy, it is not the bug that kills you- survival has become a matter of whether your cellular immune system can cope.