Evidence suggests that the epidermal growth factor receptor (EGFR) and its ligands are involved in the pathogenesis of different human carcinomas, including breast cancer. Results of phase II clinical trials of EGFR tyrosine kinase inhibitors (TKIs) have shown that these compounds have little activity in breast cancer patients when used as single agents. The potential pitfalls of these clinical trials, and the molecular mechanisms that might be involved in regulating the sensitivity/resistance of breast cancer cells to EGFR TKIs are discussed in this brief article. In particular, preclinical findings clearly demonstrate that breast cancer cells are able to activate different mechanisms to escape the anti-tumor effects of drugs directed against growth factor-driven pathways. Therefore, it is conceivable that significant blockade of tumor growth might be obtained only through contemporary blockade of different growth promoting pathways, at least in advanced disease. In addition, preclinical and clinical findings support the use of EGFR TKIs in specific subgroups of breast cancer patients, such as estrogen receptor positive (ER+), tamoxifen resistant patients. In this regard, we describe potential future applications of these compounds in combination with other agents in the treatment of breast carcinoma.