The prevalence of obesity has dramatically increased over the past decade along with the cardiovascular and other health risks it encompasses. Adipose tissue, which is distributed in the abdominal viscera, carries a greater risk for cardiovascular disorders than adipose tissue subcutaneously. There is a sex difference in the regional fat distribution. Women have more subcutaneous fat, whereas men have more visceral fat. Therefore, obesity-related metabolic disorders are much lower in premenopausal women than men. Peripheral metabolic signals like leptin and insulin are involved in the food intake, body weight, body fat distribution, and cardiovascular disease. Key areas in the brain, including the hypothalamus, integrates these peripheral adiposity signals to maintain overall adiposity levels, and these brain regions are directly influenced by sex hormones. Therefore, differences in cardiovascular disease may be under the influence of sex hormones either directly in the brain or through their influence of body fat distribution. The role of estrogen in mediating body fat distribution and cardiovascular disease is the focus of this review.