In female mammals, liver estrogen receptor alpha (ERα) plays a central role in the adaptive response of hepatic metabolism to the energy requirements characterizing the different reproductive stages. Unlike in females, the expression of ERα in the adult male liver is very low. Although obesity is prevalent in females, fertile women are to some extent protected from obesity-associated fatty liver and cardio-metabolic disease, suggesting the involvement of estrogen signaling. Meda and colleagues highlight the essential role of hepatic ERα in the regulation of lipid metabolism in the liver of the two sexes when dietary lipids are in excess. In males, hepatic ERα action contributes to liver lipid accumulation; conversely, in females, ERα prevents the hepatic lipid deposition.