Recent findings have provided insights into pathogenic mechanism(s) that may complement and add to the traditional glutamatergic mechanisms to which ischemic brain injury is ascribed. The discovery of mechanisms leading to ionic imbalance and signaling cascades that mediate cross-talk between redundant pathways of cell death, as well as mechanisms that operate downstream of, upstream of and in parallel with excitotoxicity, has spurred new research into therapeutics ranging from proof of concept in animals to human clinical trials. This Perspective presents an integrated consideration of new molecular pathogenic mechanisms underlying ischemic damage in the brain, and how our combined knowledge of these mechanisms and our existing knowledge of excitotoxicity may establish new targets for therapy, by allowing clearer boundaries on what might be expected of a given intervention, and may yield advances that will benefit patients.