Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterised by the production of an extraordinary array of autoantibodies reactive with nuclear antigens. Interaction of these autoantibodies with their cognate antigens leads to widespread inflammatory injury and underlies the pathogenesis of SLE. The aetiology of SLE in unknown, as well as the factors that influence the severity of disease manifestations. In mice and humans, expression of autoimmunity is under complex genetic control. A strategy to analyse the contribution of individual alleles to a multigenic trait has been the development of animals carrying genetic manipulations of specific genes implicated in the pathogenesis of SLE. This approach allows an in vivo assessment of the impact on the immune system of severe modifications in the expression (deficiency or overproduction) of genes suspected to play a role in the development of an autoimmune response. Genetically manipulated models have proved to be very useful to dissect effector mechanisms involved in disease pathogenesis and/or to delineate genetic mechanisms that may lead to systemic autoimmunity. Several important observations have emerged from the genetically engineered models. First, whether a particular gene or mutation causes a disease depends on the host: both disease susceptibility and the disease phenotype that result from the alteration of a single gene depend on other genes. Second, some genetic defects may share common pathogenic pathways. As a result, one could reasonably predict the possibility of developing common therapeutic strategies to treat this multifactorial complex condition. Finally, the development of genetically manipulated animals has led to the discovery of new roles for genes with known immune functions. The complement deficient animals that will be presented in more details are a typical example of this.  There is overwhelming evidence that deficiency of classical pathway complement proteins causes the development of SLE in humans and mice.  Complement is implicated in the pathogenesis of SLE in several ways and may act as both friend and foe. Recently it has been suggested that one of the main activities of the classical pathway is to promote the resolution of inflammation by enhancing the clearance and uptake of dying cells by macrophages. We have developed a series of murine models of complement deficiency and SLE and found that these mice develop a lupus-like disease and have an impaired clearance of apoptotic cells.  We have observed a similar phagocytic defect in macrophages derived from C1q-deficient humans cultured in autologous serum. This defect was rectifiable with purified human C1q. Consistent with these findings, we have data showing that macrophages from two lupus-prone murine strains have an impaired phagocytosis of apoptotic cells when compared with two non-autoimmune strains. Collectively these data strongly support the hypothesis that deficiency in complement predisposes to the development of lupus through inefficient removal of potentially pathogenic apoptotic cell debris. However, impaired clearance of such cells is, on its own, insufficient to produce autoimmunity. The data available from knockout mice emphasize that susceptibility to an autoimmune disease might depend on many factors in addition to the defective removal of dying cells. In summary it is clear that the traditional view of the role of complement in autoimmunity needs revision. Complement activation in lupus has been viewed as a major cause of tissue injury. Instead, evidence is emerging that complement may play a protective role rather than an exclusively pro-inflammatory role in tissue injury.