Bcl-2 is an inhibitor of apoptosis and is overexpressed in more than half of all human cancers. Overexpression of Bcl-2 occurs in 40% to 80% of human breast tumors. Bcl-2 is not an independent prognostic marker in breast cancer patients, in part because most Bcl-2-positive breast cancers express estrogen and/or progesterone receptors. This positive association of Bcl-2 with hormone receptors in breast cancer may explain its apparent correlation with response to hormone therapy. However, diminished apoptotic response caused by Bcl-2 overexpression is associated with cellular resistance to chemotherapeutic drugs. Downregulation of bcl-2 by antisense oligonucleotides has been shown to improve the efficacy of chemotherapy in experimental models. Phase III randomized clinical trials are ongoing in patients with solid tumors. Bcl-2 antisense-based therapy represents a viable strategy for inducing apoptosis and enhancing the chemosensitivity of breast cancers.