Gene expression profiling of human tumors has provided a new paradigm for classifying breast carcinomas, predicting response to treatment, and risk of recurrence. Estrogen receptor (ER), human epidermal growth factor 2 (HER2) receptor, and proliferation-related genes are the main drivers of classification in many of the gene expression profiling tests for breast cancer. However, ER, progesterone receptor (PR), and HER2 receptor status remain essential in determining the need and type of adjuvant therapy. These biomarkers are routinely tested for in all invasive breast carcinomas; ER testing is also performed on cases of ductal carcinoma in situ (DCIS). This article will provide an update on current guidelines from the American Society of Clinical Oncologists (ASCO) and the College of American Pathologists (CAP) for ER and HER2 testing by immunohistochemistry (IHC) and in situ hybridization (ISH). The populations to be tested, antibody selection, criteria for interpretation, and reporting are discussed. The molecular alterations that correlate with IHC results, alternative methods of testing, and the current approach to complex aspects of HER2 testing, including heterogeneity and polysomy, also are summarized.