Breast cancer is the leading cause of cancer amongst women in the westernized world. The presence or absence of ERalpha in breast cancers is an important prognostic indicator. About 30-40% of breast cancers lack detectable ERalpha protein. ERalpha- breast cancers are resistant to endocrine therapies and have a worse prognosis than ERalpha+ breast cancers. Since expression of ERalpha is necessary for response to endocrine therapies, investigational studies are ongoing in order to understand the generation of the ERalpha- phenotype and develop interventions to restore ERalpha expression in ERalpha- breast cancers. DNA methylation and chromatin remodeling are two epigenetic mechanisms that have been linked with the lack of ERalpha expression and in these cases; demethylation of the ERalpha promoter or treatment with HDAC inhibitors shows promise in restoring ERalpha expression in ERalpha- breast cancers. Two additional potential mechanisms underlying generation of the ERalpha- phenotype involve E6-AP and Src, both of which have been shown to be elevated in ERalpha- breast cancer and can drive the proteasomal degradation of ERalpha. Recently, studies have demonstrated that upregulated growth factor signaling due to hyperactive MAPK activity significantly contributes to generation of the ERalpha- phenotype and that inhibition of MAPK activity can cause re-expression of the ERalpha and restore sensitivity to endocrine therapies. Given the challenges in treating ERalpha- breast cancer, understanding and manipulating the cellular mechanisms that effect expression of ERalpha are imperative in order to restore sensitivity to endocrine therapies and to design novel therapeutics for the treatment of ERalpha- breast cancers.