The HER2/neu proto-oncogene encodes a 185-kd transmembrane receptor with tyrosine kinase activity. Amplification of HER2 with overexpression of the p185HER2 receptor occurs in 20%-30% of breast cancers and has been established as an independent prognostic factor in numerous studies. Increasing evidence suggests that HER2 may be a predictive marker for response to chemotherapy and hormonal therapy. HER2 overexpression has provided a new target in breast cancer therapy, as evidenced by the development of trastuzumab (Herceptin(R)), a monoclonal antibody targeted against HER2. Detection of HER2 in the clinical setting is performed by immunohistochemistry or fluorescence in situ hybridization in tissue, and by detection of the shed extracellular domain in serum or plasma. Differences in methodology, reagents, and scoring systems have led to varying results in different patient cohorts, contributing to the debate on the role of HER2 as a prognostic and predictive factor. This review focuses on the prognostic and predictive value of serum HER2 detection in the management of HER2-positive breast cancer.