<p>Oestradiol (E2), a steroid hormone derived from cholesterol, has long been recognized for its central role in female reproduction and pathobiology of menopause. However, accumulating evidence underscores a critical role for E2 in the regulation of systemic metabolism in both women and men. The metabolic actions of E2 are predominantly mediated by oestrogen receptor α (encoded by <i>ESR1</i>), a nuclear receptor with heritable expression patterns and tissue-specific transcript levels highly correlated with indices of metabolic health in both sexes. Here we provide an overview of the cell-specific actions of E2 and its receptors (α and β) in modulating key metabolic pathways. We contextualize these mechanistic preclinical studies with epidemiological data linking the menopausal transition to a marked rise of metabolic disease risk and provide evidence that E2 replacement mitigates this risk by preserving metabolic health.</p>