Human epidermal growth factor receptor 2 (HER-2) is over-expressed in 15% to 30% of breast cancers and is a poor prognostic marker in node-positive patients. HER-2 expression is an indicator of greater sensitivity to anthracycline-based chemotherapy and is the major criterion for selection for treatment with the anti-HER-2 antibody trastuzumab (Herceptin). Fluorescence in situ hybridization and immunohistochemistry (IHC) are the 2 most commonly used methods for detection of the gene and protein, respectively. Criticisms have been levied at the IHC method of identifying HER-2 overexpression but convenience and costs of this technique cannot be overlooked. Modifications to the IHC technique and scoring accommodate for many of the problems that derive from variables in preanalytical and analytic factors that influence results but standardization is currently impossible to attain. Deficiencies in fluorescence in situ hybridization assay also exist and alternative molecular methods of assay are explored in this review.