The complement system is one of the key players in the defence against infections. Its activation during the innate immune response leads to the generation of several proteins that contribute to the lysis and opsonization of microorganisms, regulate inflammatory reactions and bridge innate immunity with the subsequent adaptive immune response. Complement is also activated in overwhelming bacterial infections that lead to sepsis, and its protective functions play a role in this frequently lethal disorder. However, despite its role in protection, complement can also contribute to the development of severe complications that significantly worsen the prognosis of septic patients. Therefore, an understanding of the mechanisms involved in the activation of complement during sepsis is essential to our efforts to introduce rational therapies targeting complement to the treatment of patients suffering from this condition. This review presents a current view of the mechanisms involved in the activation of complement in sepsis, in the context of the multiple interactions between complement and other biological systems that are involved in the pathogenesis of this disorder.