Sex differences in the onset and manifestation of cardiovascular disease are well described, yet the mechanism(s) underlying these clinical observations remain inadequately understood. Estradiol (E2) exerting its effects through receptors in responsive tissues has been shown to protect the heart from cytotoxic, ischemic, and hypertrophic stressors; however, the actions of this hormone are complex and remain inadequately understood. Although the modulatory effects of E2 on vascular endothelium and the heart are well-defined, receptor mediated action on cardiomyocytes, specifically estrogen receptor alpha (ER), lacks a mechanistic understanding and requires further resolution. Here we show that that Esr1, the gene that encodes ER, is crucial in the maintenance of cardiac functional capability and is essential for mitochondrial from and function including membrane architecture, energy homeostasis, metabolic flexibility, and substrate metabolism.