There is abundant evidence that infectious sepsis both in humans and mice with polymicrobial sepsis results in robust activation of complement. Major complement activation products involved in sepsis include C5a anaphylatoxin and its receptors (C5aR1 and C5aR2) and, perhaps, the terminal complement activation product, C5b-9. These products (and others) also cause dysfunction of the innate immune system, with exaggerated early proinflammatory responses, followed by decline of the innate immune system, leading to immunosuppression and multiorgan dysfunction. Generation of C5a during sepsis also leads to activation of neutrophils and macrophages and ultimate appearance of extracellular histones, which have powerful proinflammatory and prothrombotic activities. The distal complement activation product, C5b-9, triggers intracellular Ca 2+ fluxes in epithelial and endothelial cells. Histones activate the NLRP3 inflammasome, products of which can damage cells. C5a also activates MAPKs and Akt signaling pathways in cardiomyocytes, causing buildup of [Ca 2+] i, defective action potentials and substantial cell dysfunction, resulting in cardiac and other organ dysfunction. Cardiac dysfunction can be quantitated by ECHO-Doppler parameters. In vivo interventions that block these complement-dependent products responsible for organ dysfunction in sepsis reduce the intensity of sepsis. The obvious targets in sepsis are C5a and its receptors, histones, and perhaps the MAPK pathways. Blockade of C5 has been considered in sepsis, but the FDA-approved antibody (eculizumab) is known to compromise defenses against neisseria and pneumonococcal bacteria, and requires immunization before the mAb to C5 can be used clinically. Small molecular blocking agents for C5aRs are currently in development and may be therapeutically effective for treatment of sepsis.