Ischemic stroke triggers a complex and highly interconnected cascade of cellular and molecular events. Early events induced following ischemic injury, including excitotoxicity, calcium overload and oxidative stress, rapidly result in cell death in the infarct core. Later events, such as neuroinflammation and apoptosis, are relevant to the death of the ischemic penumbra. Drugs that limit delayed-injury events have a wide therapeutic window for protection; however, the damaging events of the ischemic cascade will eventually prevail if reperfusion is not achieved within minutes after ischemia. The combination of thrombolytics with protective drugs may provide a promising therapy in the management of stroke. Targeting all components of the neurovascular unit, rather than just the neuron, should be a priority in stroke research, and agents that block multiple events of the injury cascade are more likely to provide cerebroprotection. Understanding when the brain begins the transition from injury to repair could have important implications for stroke therapy. Several ischemic mediators have dual roles, with detrimental acute effects, but beneficial effects in the repair phase; therefore, extending experimental stroke investigations to an analysis of the long-term outcome is important. This review provides a critical evaluation of promising therapeutic strategies for ischemic stroke, and a translational perspective on how to improve success in the development of novel pharmaceuticals for cerebral ischemia.