Breast tumors expressing estrogen receptor alpha (ER) respond well to therapeutic strategies using SERMs (selective estrogen receptor modulators) such as tamoxifen. However, about thirty percent of invasive breast cancers are hormone independent because they lack ER expression due to hypermethylation of ER promoter. Treatment of ER-negative breast cancer cells with demethylating agents and histone deacetylase inhibitors leads to expression of ER mRNA and functional protein. Additionally, growth factor signaling pathways have also been implicated in ER silencing in ER-negative tumor phenotype. Recently, important role of components of ubiquitin-proteasome pathway has been shown in mediating downregulation of ER. In this article, we will review various mechanisms underlying the silencing of ER in ER negative tumor phenotype and discuss diverse strategies to combat it. Ongoing studies may provide the mechanistic insight to design therapeutic strategies directed towards epigenetic and non-epigenetic mechanisms in the prevention or treatment of ER-negative breast cancer.