Since the cloning of the estrogen receptor alpha (ERalpha) and subsequent identification of a second distinct form of ER, termed ERbeta, a large volume of research has begun to define the molecular mechanisms of ER action. However, although great progress has been made, ER action is still poorly understood. It is expected that a better understanding of ER action may lead to novel strategies and targets for breast cancer prevention and treatment. One of the early-realized functions of the ER was regulation of growth factor signaling, but the degree of interaction between these two mitogenic signaling pathways could not have been anticipated. Recent evidence suggests that the ER and the growth-factor-signaling pathways intersect and directly interact at every level of signal transduction. The resulting synergism between ER and growth factors has been documented both in normal breast development and, importantly, in breast cancer progression and antiestrogen resistance. In this review, we will highlight our current understanding of the molecular mechanisms of cross-talk between ER and growth-factor-signaling pathways.