Clinical laboratory testing for human epidermal growth factor receptor-2 (HER2) in patients with newly diagnosed breast and gastric cancer is critically important for therapeutic decisions about adjuvant treatment. The HER2 pathway is a major molecular driver of disease progression in a subset of these solid tumors and the results of HER2 testing determine which patients are likely to respond to an expanding variety of therapies that target this important biologic pathway. Given the significant clinical impact of these test results on patient management and adjuvant treatment decisions, standardization of the assay for HER2 and assured reliability of these results are critical. We review highlights of the clinical rationale that underlies HER2 testing for both breast and gastric carcinomas, and describe some of the challenges associated with ensuring accurate test results.