The alternative pathway of complement is receiving increasing attention as a therapeutic target because of recent findings in several animal models that support its essential role in tissue injury and disease pathogenesis. Although the contribution of alternative pathway activation to serum complement activation in vitro is relatively modest, its role in generating activated pro-inflammatory fragments at extra-vascular sites is substantial. Several potential mechanisms might underlie this exaggerated effect, including local synthesis of alternative pathway components, disease-induced alterations of regulatory proteins, and influx of inflammatory cells that contain alternative pathway components into sites of injury. This review examines several animal models in which the alternative pathway is centrally involved in disease pathogenesis and which suggest a potential role for alternative pathway inhibitors as therapies for human disease. It is also expected that several clinically relevant studies will be presented at the XXth International Complement Workshop that will identify additional areas of interest with regard to this pathway.