Targeting the estrogen receptor is an important strategy in breast cancer therapy. However, although inhibiting estrogen receptor function with specific estrogen receptor modulators can achieve a primary response in cancer patients, intrinsic or subsequently acquired resistance to the therapy remains a major obstacle in the clinic. Thus, it is critical to gain a more thorough understanding of how estrogen receptor functions are regulated in breast cancer.Here, we demonstrate that the non-receptor tyrosine kinase c-ABL is a functional partner of the estrogen receptor, as expression of c-ABL sustained transcriptional activity of the estrogen receptor. More importantly, inhibition of c-ABL resulted in sensitization to treatment by tamoxifen (TAM) in estrogen receptor-positive breast cancer cells, as manifested by inhibition of cell survival and suppression of anchorage-independent growth. We found that c-ABL interacts with estrogen receptor in breast cancer cells and that expression of c-ABL is a frequent event in primary breast cancer tumor tissues. In estrogen receptor-positive tumors, the expression of c-ABL significantly correlated with disease progression and metastasis. This study shows that c-ABL regulates the cellular response to TAM through functional interaction with the estrogen receptor, which suggests c-ABL as a therapeutic target and a prognostic tumor marker for breast cancer.