Astrocytes are critical regulators of neuronal function and an effective target for stroke therapy in animal models. Identifying individual targets with the potential for simultaneous activation of multiple downstream pathways that regulate astrocyte homeostasis may be a necessary element for successful clinical translation. Mitochondria and microRNAs each represent individual targets with multi-modal therapeutic potential. Mitochondria regulate metabolism and apoptosis, while microRNAs have the capacity to bind and inhibit numerous mRNAs. By combining strategies targeted at maintaining astrocyte function during and following cerebral ischemia, a synergistic therapeutic effect may be achieved.