Estrogen is essential for growth and development of the mammary glands and has been associated with the promotion and growth of breast cancer and in line with this, most human breast cancers are initially estrogen-dependent and undergo regression when deprived of their supporting hormone. Estrogen exerts many of its effects via two nuclear estrogen receptors (ERs), ERα and ERβ. The discovery of a second ER, ERβ, demanded a full re-evaluation of estrogen action in all target tissues and different estrogen associated diseases, including human breast cancer. However, despite over 15 years of research, the exact role, if any, of ERβ in human breast cancer remains elusive. The main challenges now are to develop highly selective anti-ERβ antibodies that are applied to large well characterized human breast cancer samples to validate their diagnostic potential and to explore ERβ-selective agonists in animal models of breast cancer to validate their therapeutic potential.