The development of a suitable neuroprotective agent to treat ischemic stroke has failed when transitioned to the clinical setting. An understanding of the molecular mechanisms involved in neuronal injury during ischemic stroke is important, but must be placed in the clinical context. Current therapeutic targets have focused on the preservation of the ischemic penumbra in the hope of improving clinical outcomes. Unfortunately, most patients in the ultra-early time windows harbor penumbra but have tremendous variability in the size of the core infarct, the ultimate predictor of prognosis. Understanding this variability may allow for proper patient selection that may better correlate to bench models. Reperfusion therapies are rapidly evolving and have been shown to improve clinical outcomes. The use of neuroprotective agents to prolong time windows prior to reperfusion or to prevent reperfusion injury may present future therapeutic targets for the treatment of ischemic stroke. We review the molecular pathways and the clinical context from which future targets may be identified.