This review focuses on mechanisms and emerging concepts that drive the science of stroke in a therapeutic direction. Once considered exclusively a disorder of blood vessels, growing evidence has led to the realization that the biological processes underlying stroke are driven by the interaction of neurons, glia, vascular cells, and matrix components, which actively participate in mechanisms of tissue injury and repair. As new targets are identified, new opportunities emerge that build on an appreciation of acute cellular events acting in a broader context of ongoing destructive, protective, and reparative processes. The burden of disease is great, and its magnitude widens as a role for blood vessels and stroke in vascular and nonvascular dementias becomes more clearly established. This review then poses a number of fundamental questions, the answers to which may generate new directions for research and possibly new treatments that could reduce the impact of this enormous economic and societal burden.