Most women with breast cancer that overexpresses either estrogen (ER+) or progesterone receptors (PR+) will be treated with an endocrine agent. Although ER and PR are the only validated predictive markers of response to hormonal therapy, many women with hormone receptor-positive (HR+) tumors will fail to respond to endocrine treatment or develop hormone resistant disease. Another tumor marker, HER-2/neu, is an oncogene whose amplification or protein overexpression predicts response to a monoclonal antibody targeting HER-2/neu, as well as to anthracycline-based chemotherapy. Preclinical and some clinical data suggest that HER-2/neu positivity may also predict for relative resistance to endocrine therapy. Interpretation of clinical data addressing this issue is confounded by largely retrospective study designs and considerable heterogeneity in patient populations and methods of marker detection and interpretation. At this writing, HER-2/neu expression should not influence the decision to use endocrine therapy.