For estrogen to function as master regulator of the bioenergetic system in the female brain, estrogen must be integrating nuclear and mitochondrial genomic responses. Further, from a systems level perspective, it would be necessary for estrogen to also regulate cytoplasmic signaling mechanisms for real time feedback on the functional outcomes of nuclear and mitochondrial gene transcription. The fundamental issues to be investigated are the mechanisms whereby estrogen integrates bioenergetic responses across two genomic compartments while simultaneously monitoring energetic demand and performance in real time. Estrogenic control of the bioenergetic system of the brain and the dismantling thereof has basic, translational and clinical significance.