From classical gland-based endocrinology to nuclear hormone receptor biology, tremendous progress has been made in our understanding of hormone responses underlying cellular communication. Estrogen elicits a myriad of biological processes in reproductive and peripheral target tissues through its interaction with the estrogen receptors ERα and ERβ. However, our knowledge of estrogen-dependent and independent action has mainly focused on ERα, leaving the role of ERβ obscure. This review discusses our current understanding of ERβ function and the emerging role of intracellular signals that act upon and achieve estrogen-like effects through phosphorylation of ERβ protein. Improving our understanding of how cellular determinants impact estrogen receptor actions will likely lead to treatment strategies for related endocrine diseases affecting women's health.