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 ERalpha and ERbeta. However, our knowledge of estrogen-dependent and independent action has mainly focused on ERalpha, leaving the role of ERbeta obscure. This review discusses our current understanding of ERbeta function and the emerging role of intracellular signals that act upon and achieve estrogen-like effects through phosphorylation of ERbeta 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.