Estrogen deprivation (ED) either as a result of a natural or artificial menopause or the use of aromatase inhibitors in postmenopausal women results in a reduction of the incidence of breast cancer. Two major clinical trials of this approach comparing anastrozole or exemestane with placebo are currently in progress to test their efficacy for prevention. Reduction of contralateral breast lesions by at least 50% compared with tamoxifen indicate this approach has promise. The target lesion within the breast for ED is not known but we argue that hyperplastic enlarged lobular units (HELUs) as well as more advanced lesions are good candidates. A major problem for ED is de novo or acquired resistance to its effectiveness. We discuss potential mechanisms of resistance including high concentrations of tissue estrogens, increase in growth factor, and signal transduction pathways within the epithelial cell and activation of paracrine pathways from breast adipocytes, macrophages and fibroblasts. It may be possible to increase effectiveness of ED by additional preventive agents or by lifestyle alterations.