ErbB3 interacts with erbB2 to activate signaling pathways leading to multi-drug resistance in breast cancer. Hetero-dimerization of erbB2 and erbB3 is able to induce activation of multiple downstream signaling pathways. In both luminal B and erbB2+ subtypes of human breast cancer, erbB2/erbB3 association may recruit IGF-1R to form a trimeric complex activating PI-3 K/Akt signaling and Src kinase and resulting in trastuzumab resistance. In erbB2+ breast cancer, interaction between erbB2 and erbB3 upregulates Survivin via a PI-3 K/Akt-dependent mechanism, and thereby confers paclitaxel resistance. In luminal B breast cancer, the erbB2/erbB3 hetero-dimers modulate ERα phosphorylation (activation) mainly through MEK/MAPK and/or PI-3 K/Akt signaling pathways, and subsequently alter tamoxifen sensitivity. These data support the hypothesis that targeting of erbB3 will significantly enhance the efficacy of those commonly used therapeutics in the treatment of erbB2+ breast cancer.