Tamoxifen is the most commonly prescribed endocrine therapy for the treatment of patients with estrogen receptor (ERα)-positive breast cancer. Unfortunately up to 40% of patients fail tamoxifen therapy. The exact molecular basis of tamoxifen action remains poorly understood and as a consequence clinicians lack reliable tumor markers to predict patient response to tamoxifen. In breast tumor cells, the EGFR family member HER4 is proteolytically processed at the cell surface to release an independently signaling intracellular domain (4ICD) that functions as both an ERα coactivator and a pro-apoptotic BH3-only protein. Naresh and colleagues found that suppressed HER4/4ICD expression in several breast tumor cell lines was associated with tamoxifen resistance. They further show that tamoxifen induces breast tumor apoptosis by disrupting the ERα/4ICDcoactivator thereby releasing 4ICD from the nuclear compartment. Subsequent mitochondrial localization of 4ICD results in activation of 4ICD BH3domain–mediated cell killing. Reintroduction of HER4 into tamoxifen resistant cell lines restores tamoxifen sensitivity in vivo, and this activity requires an intact 4ICD BH3 domain (xenograft). Clinically, each breast cancer patient with an ERα-positive tumor and nuclear coexpression of the 4ICD coactivator responded to tamoxifen (nuclear 4ICD immunohistochemistry and Kaplan-Meier curves). These data provide a clinically important role for 4ICD as a unique effector of tamoxifen action in breast cancer, and support clinical evaluation of 4ICD expression as a tumor marker predicting patient response to tamoxifen therapy. For details, see the article by Naresh et al. on page 6387 of this issue.