Natural selection clearly favors the accumulation and storage of lipids in humans, predisposing women to store excess fat in gluteal regions and predisposing males to store excess fat in visceral regions. In addition, gender differences are reported with respect to the concentrations of circulating lipids and lipoproteins, with lower concentrations of total cholesterol and low density lipoprotein (LDL)-cholesterol in premenopausal women than in men. This latter evidence renders gender differences in fat distribution and whole-body lipid metabolism of particular interest with respect to the incidence and prevalence of human diseases. Although the mechanisms underlying gender-related differences in body fat distribution and lipid homeostasis remain to be fully determined, the reported differences appear to principally reflect the actions of the sex steroid hormone estrogen on whole-body lipid metabolism. In the present review, we dissect the role played by 17β-estradiol, the most active between estrogens, and by its receptors in regulating lipid homeostasis in adipose tissue, liver, and brain, evaluating the potential impact of this hormone in preventing lipid abnormalities.