Endocrine resistance is a major limitation to the successful treatment of estrogen receptor-positive (ER(+)) breast cancer, and the EGFR (epidermal growth factor receptor) and ErbB-2 receptor tyrosine kinases are involved in this process. A recent study now implicates the other two ErbB family members, ErbB-3 and -4. Exposure of ER+ breast cancer cells to the pure antiestrogen, fulvestrant, increased levels of ErbB-3 or ErbB-4 and sensitivity to the growth-stimulatory effects of heregulin β1, a potent ligand for these receptors. Thus, the initial growth-inhibitory effects of fulvestrant appear compromised by cellular plasticity that allows rapid compensatory growth stimulation via ErbB-3/4. Further evaluation of pan-ErbB receptor inhibitors in endocrine-resistant disease appears warranted.