Considerable interest has been focused on elucidating the pathogenesis of progressive cell death following stroke, and more recently on identifying the mechanisms responsible for tissue repair/recovery, in hopes of identifying relevant therapeutic targets. One potential target that has received increasing attention is the complement cascade. Despite initial data suggesting that complement-mediated cerebral injury was principally mediated through C1q, subsequent studies in deletionally mutant mice and non-human primates suggest that complete C3 blockade is critical for neuroprotection in adult animals. Unfortunately, only recently have we been able to generate specific C3 inhibitors. These tools, together with an increasing appreciation that complement, and specifically C3, play an important role in the clearance of dead/dying cells, as well in endogenous neurogenesis, lead us to hypothesize: (1) that C3 activation results in progressive tissue injury in the hours following stroke, but that ultimately its role in cell clearance and neurogenesis may exert positive effects on functional outcome, and (2) that carefully tailored, and highly specific, anti-C3 strategies will ultimately prove safer and more efficacious than non-specific strategies especially when administered together with routinely utilized anti-platelet, anti-thrombotic and fibrinolytic medications. To address these hypotheses, with the goal of developing clinically relevant therapies, experiments will: (1) investigate whether the neuroprotective effect of C3 blockade is predominantly mediated through C3a-C3a receptor, and (2) examine to what degree, and under what conditions C3-blockade alters: (a) apoptotic/necrotic cell clearance, (b) the resolution of inflammation, and (c) endogenous neurogenesis.