The complement system is a multi-tasking gatekeeper of innate immunity that intricately interacts with other key defense systems, such as the endothelial barrier, contact activation and coagulation systems, in maintaining tissue immunosurveillance and homeostasis. Its rapid and forceful activation in the bloodstream not only ensures the effective containment of microbial infections through potent cytolytic mechanisms, but also alerts the adaptive immune compartment to ensure the mounting of a proper humoral immune response against foreign antigens. However, there is a lurking ‘dark side’ that can lead complement astray, fueling a self-perpetuating vicious cycle of inflammation, exuberant immune activation and irreversible tissue injury that collectively exacerbate both acute and chronic pathologies. Indeed, complement dysregulation or excessive activation have been widely recognized as key pathogenic drivers in a wide spectrum of inflammatory or immune-mediated diseases. Targeted modulation of the complement system at various points of the cascade has revealed promising therapeutic targets for ameliorating disease scores in a number of conditions ranging from ocular, neurodegenerative and thromboinflammatory disorders, to cancer, periodontal diseases, chronic hemolytic anemias, ischemia-reperfusion organ injury, antibody-mediated transplant rejection and hemodialysis-triggered inflammation.