The complement (C) system comprises some 15 soluble plasma proteins that interact with one another in three distinct enzymatic activation cascades (the classical, alternative, and lectin pathways) and in the nonenzymatic membrane attack pathway. C is an important component of the host innate immune system. This chapter reviews briefly the main situations in vivo where C may cause disease, discusses recent strategies for regulating C activation in order to reduce C-mediated pathology, and addresses the potential problems related to therapies that inhibit the physiological effects of C activation. Harm will result when C activation occurs in an uncontrolled manner and/or at an inappropriate site; the end result of this will be inflammation and tissue destruction. "Iatrogenic" (treatment-precipitated) C activation is a common consequence of the many modern therapies that involve contact of blood with a foreign surface. The naturally occurring C regulators are excellent inhibitors of C and have potential as therapeutic agents. Inhibitors acting in the terminal pathway are less likely to predispose to bacterial infections and immune complex disease, particularly when used for long-term therapy. With the realization that hyperacute rejection was mediated by C attack came the suggestion that the human C regulators might be utilized to overcome this hurdle. The simplest approach to protecting the xenograft would be to utilize the fluid-phase C regulators. A xenograft hyperexpressing human membrane cofactor protein (MCP) might be rendered highly susceptible to infection with measles virus with consequences for the graft that are not predictable from current knowledge.