The HER2 (ERBB2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major biomarker of invasive breast cancer and target of therapy for the disease. HER2 gene amplification or protein overexpression is encountered in approximately 20% of newly diagnosed breast cancers and is a validated adverse prognostic factor with a mean relative risk for overall survival of 2.74. A series of quality assurance recommendations for the marketed slide-based HER2 testing approaches including immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH/SISH) has recently been published by the American Society of Clini- cal Oncology - College of American Pathologists (ASCO-CAP). Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER2 testing and emerging novel HER2 testing techniques, including messenger RNA (mRNA)-based testing by real time polymerase chain reaction (RT-PCR) and DNA microarray methods, HER2 receptor dimerization, phosphorylated HER2 receptors and HER2 status in circulating tumor cells are of current interest in the management of breast cancer. Also of significant interest are the evolving lists of biomarkers proposed to predict resistance to the major anti-HER2 therapies, trastuzumab and lapatinib.