Numerous failures in clinical stroke trials have led to some pessimism in the field. This short review examines the following questions: Can experimental models of stroke be validated? How can combination stroke therapies be productively pursued? Can we achieve neuroprotection without reperfusion? And finally, can we move from a pure neurobiology view of stroke towards a more integrative approach targeting all cell types within the entire neurovascular unit? Emerging data from both experimental models and clinical findings suggest that neurovascular mechanisms may provide new opportunities for treating stroke. Ultimately, both bench-to-bedside and bedside-back-to-bench interactions may be required to overcome the translational hurdles for this challenging disease.