The complement system has once again come into prominence in the therapeutic development arena. The recent approval of an inhibitory monoclonal antibody, eculizumab, which is directed against complement component C5 for the disease paroxysmal nocturnal hemoglobinuria has provided the initial validation of this system as a therapeutic target. Preclinical studies using animal models and human-derived samples demonstrate that inhibition of complement ameliorates many inflammatory and autoimmune disease manifestations. Major efforts continue to define the most optimal means to block complement activation in a cost-effective manner. Because the system is initiated through three pathways and generates at least six immunoregulatory and pro-inflammatory mediators, there is substantial complexity to this problem. One pathway, designated the alternative pathway, has recently been shown to play a particularly important role in preclinical disease models. Further evidence of the importance of the alternative pathway has been provided by studies of human diseases, where mutations or dysfunctional polymorphisms that promote activation of this pathway are highly associated with the diseases atypical hemolytic uremic syndrome, dense deposit disease, and age-related macular degeneration. This article reviews evidence in support of the essential role of the alternative pathway in the generation of tissue injury and the rationale for development of therapies that modulate its activity.