The complement system is a central homeostatic system of the vertebrate organism and part f innate immunity. When activated, complement has multiple functions and drives homeostasis and the elimination of infectious microbes (Walport MJ (2001) N Engl J Med 344:1140-1144; Zipfel PF, Skerka C (2009) Nat Rev Immunol 9:729-740). Several inflammatory disorders are caused by defective complement action, and the growing, detailed understanding of the underlying pathophysiological principles translate into therapy with complement inhibitors. As complement inhibitors have been pproved for treatment of the complement-mediated disorders hemolytic uremic syndrome (HUS) and paroxysmal nocturnal hemoglobinuria (PNH), there is a growing interest to extended and improve the options for other complement-mediated diseases. Here, we summarize the current understanding and concepts how defective complement action at biological surfaces lead to pathology and disease, and how this understanding can be used for the development of surface targeting complement inhibitors.