The metabolic syndrome has reached pandemic level worldwide, and evidence is that estradiol plays a key role in its development. The discovery of the second estrogen receptor, ERβ, in tissues previously not considered targets of estradiol was a breakthrough in endocrinology. In the present review, we discuss how the presence of ERβ and the previously described ERα in tissues involved in glucose and lipid homeostasis (brain, skeletal muscle, adipose tissue, pancreas, liver, and heart) may have important implications to risk factors associated with the metabolic syndrome. Imbalance of ERα/ERβ ratio in this "metabolic network" may lead to the metabolic syndrome.