Sepsis represents a lethal complication of major trauma, characterized by an uncontrolled complement activation, as determined by significantly elevated plasma levels of C3a, C4a and C5a [176] [177] [178] . The anaphylatoxin C5a appears to represent the central molecule in the development of the overwhelming inflammatory response in sepsis, and has been coherently described as "too much of a good thing" [179] [180] [181] (Figure 4 ). Blockade of C5a was linked to improved survival in different experimental models of sepsis [182] [183] [184] [185] . Persistent elevation of C5a during progressive sepsis was related to a posttraumatic immunparalysis with "shutdown" of crucial neutrophil functions, including a loss of chemotactic and phagocytotic activity, impairment of the oxidative burst, and disturbances in intracellular signaling pathways [48, 186, 187] . Recent studies corroborated an important contribution of C5a in modulating apoptosis in different cell types during sepsis. While apoptosis rates in neutrophils were shown to be significantly attenuated during sepsis, lymphocytes, thymocytes and adrenal medullary cells exhibited increased C5a-dependent susceptibility to programmed cell death [188] [189] [190] [191] [192] . The latter phenomenon was hypothesized to be responsible for impaired adreno-medullary catecholamine release predisposing the development of septic shock [191] . Excessive C5a levels during sepsis were furthermore associated with reduced myocardial contractility and cardiac output, a phenomenon described as "cardiomyopathy of sepsis" [193] . In general, multiple organs seem to be put at increased risk for C5a-mediated damage induced by an abrupt upregulation of the C5aR in a variety of tissues (heart, lung, kidney, liver, thymus) in early phases of sepsis [194, 195] . A recent study implied that C5a-mediated signaling through the two C5a receptors (CD88 and C5L2) contributes to adverse outcome from sepsis [196, 197] . In experimental models of sepsis, the blockade of C5a and its receptors has been shown to protect end-organ function and to improve outcomes, thus providing a future new avenue for pharmacological treatment of this detrimental complication of major trauma [198] [199] [200] [201] . Future studies will have to be designed to validate this promising notion in a clinical setting.