In women with estrogen receptor(ER)- and ErbB2(HER2)-positive breast cancer, a vicious cycle is established between ER mechanisms of action and the growth factor receptor network, leading to enhanced cell proliferation and endocrine resistance. As such, co-targeting ErbB1 and ErbB2 with lapatinib in combination with hormonal therapy is an attractive approach to enhance the efficacy of either tamoxifen or estrogen deprivation. As demonstrated in the EGF30008 trial, a combined targeted strategy with letrozole and lapatinib significantly increased progression-free survival and clinical benefit rates in patients with metastatic breast cancer that co-expresses ER and ErbB2. Therefore, women who are not in an acutely life-threatening situation should be considered for upfront treatment with hormonal therapy (e. g. aromatase inhibitors) in combination with an anti-ErbB2 therapy.