Estrogens regulate function of reproductive and non-reproductive tissues in healthy and diseased states including breast cancer. They mainly work through estrogen receptor alpha (ERα) and/or estrogen receptor beta (ERβ). There are various ERα targeting agents that have been used for treatment of ER (+) breast tumors. The impact of direct nuclear activity of ER is very well characterized in ER (+) breast cancers and development and progression of endocrine resistance. Recent studies also suggested important roles for extranuclear-initiated ERα pathways, which would decrease the potency and efficiency of ERα targeting agents. In this mini-review, we will discuss the role of nuclear and extra-nuclear ER signaling and how they relate to therapy resistance in breast cancer.