Emerging results from clinical trials with epidermal growth factor receptor (EGFR) inhibitors indicate good tolerability and, at best, modest to no clinical activity in a variety of epithelial tumors, including breast carcinomas. Although the EGFR is widely expressed in epithelial cancers, there is no evidence of frequent EGFR alterations at the DNA level in human tumors. This lack of molecular evidence to suggest a pathogenic role for the EGFR in breast cancer questions the notion that use of single-agent EGFR inhibitors in this disease is a viable therapeutic approach. The lack of selection of EGFR-dependent breast tumors into trials with EGFR inhibitors suggests the possibility that these were not true-negative studies. A point of view regarding challenges in the development of anti-EGFR therapies for patients with breast cancer and possible approaches to overcome them is presented in this article.