As a leading cause of death in the world, cerebral ischemic stroke has limited treatment options. The lack of glucose and oxygen after stroke is particularly harmful in the brain because neuronal metabolism accounts for significantly more energy consumption per gram of body weight compared to other organs. Our laboratory has identified mitochondrial metabolism of astrocytes to be a key target for pharmacologic intervention, not only because astrocytes play a central role in regulating brain metabolism, but also because they are essential for neuronal health and support. Here we review current literature pertaining to the pathobiology of stroke, along with the role of astrocytes and metabolism in stroke. We also discuss our research, which has revealed that pharmacologic stimulation of metabotropic P2Y1 receptor signaling in astrocytes can increase mitochondrial energy production and also reduce damage after stroke.