Estrogen and its receptor (ER) are critical for development and progression of breast cancer. This pathway is targeted by endocrine therapies that either block ER functions or deplete ER's estrogen ligand. While endocrine therapies are very effective, de novo and acquired resistance are still common. Laboratory and clinical data now indicate that bidirectional molecular crosstalk between nuclear or membrane ER and growth factor receptor pathways such as HER2/neu is involved in endocrine resistance. Preclinical data suggest that blockade of selected growth factor receptor signaling can overcome this type of resistance, and this strategy is already being tested in clinical trials.