Despite the primary role of estrogen receptor α (ERα) in mediating the effects of estrogen in malignant breast and as therapeutic target, the development of endocrine-resistant and metastatic phenotypes indicates the complexity of the mechanisms that regulate hormone signaling in the disease. The discovery of ERβ and its functional characterization has improved our understanding about the mechanism of estrogen receptor action, the regulation of estrogen signaling in breast tumors, and their response to therapy. The progressive decline of ERβ in pro-invasive lesions and invasive tumors points toward a role as suppressor of both tumorigenesis and progression in breast cancer. The antiproliferative and anti-invasive effects of the receptor and its agonists in preclinical models of breast cancer support these roles and delineate the mechanisms of action. The association of ERβ with clinical outcome proposes the potential use of the receptor as prognostic marker and its agonists in chemoprevention and therapeutic strategies for resistant and metastatic disease.