There is increasing evidence that the complement system plays an important role in tissue damage associated with trauma and ischemia. In the present review we focus on some principles of importance for a basic understanding of the complement system, particularly aimed at those not working in this field. Complement is activated by its ability to discriminate between self and non-self, primarily as a defense against microorganisms. The activation induces an inflammatory reaction which may lead to harmful effects on the host, either as local tissue damage or, in case of an extensive systemic activation, as breakdown of homeostatic mechanisms. Complement-mediated inflammation is important not only in specific immunological defense reactions, but also in the induction of tissue injury by ischemia, hypothermia or other general tissue-damaging factors. Major trauma leads to systemic complement activation and complications to trauma may enhance the activation and increase the risk of development of the whole body inflammatory reaction and even of a fatal outcome. To protect the host against self-damage, complement activation is controlled by a series of regulatory proteins inhibiting at the various levels of the cascade. Intervening with complement activation using regulatory proteins like soluble complement receptor 1 has provided direct evidence for the importance of complement in tissue damage in various experimental models. Therapeutic complement intervention using a similar approach may be a useful tool in selected patients to attenuate the degree of complement activation and thereby reduce the total inflammatory load.