Although classical concepts had assigned priority to the nuclear-initiated steroid signaling pathway of estrogen receptor (ER), recent studies document that the ER also possesses the membrane-initiated steroid signaling (MISS) pathway. A small fraction of ER is associated with the cell membrane and mediates the rapid effects of estrogen. Unlike classical growth factor receptors, such as insulinlike growth factor 1 receptor and epidermal growth factor receptor, ER has no transmembrane and kinase domains. Instead, the initiating signals of MISS action of ER require a rapid formation of ER-centered protein complexes with many signaling molecules, leading to the activation of mitogen-activated protein kinase and Akt signaling pathways. In this review, we focus on the MISS action of ER and its role in the development of hormone resistance in breast cancer. A full understanding of the mechanisms, with the ultimate aim of abrogating specific steps, should lead to more targeted strategies for treatment of hormone-dependent breast cancer.