Resistance to anti-HER2 targeted therapy imposes a crucial limitation to the successful treatment of HER2 positive breast cancer. The expression of HER4 and its prognostic value is controversial in breast cancer. The role of HER4 in trastuzumab treatment and resistance in HER2-positive breast cancer has been recently studied. HER4 activation, cleavage and nuclear translocation have been demonstrated mediate trastuzumab resistance in HER2 positive breast cancer. In addition, nuclear HER4 is suggested could be a novel predictive and prognostic biomarker in HER2 positive breast cancer patients. Understanding the role of HER4 may offer useful insights to cancer treatment in HER2-positive breast cancer and other cancers.