This past decade has witnessed the remarkable advances in the understanding of the role of the erbB2 gene in cancers and the stunning progress in developing targeted therapies for erbB2-overexpressing cancers. Activation of the ErbB2 receptor signaling pathways can enhance various metastasis-associated properties that lead to an increase of cancer metastasis. Additionally, ErbB2 overexpression confers therapeutic resistance via receptor-mediated antiapoptotic signals. To limit these disastrous effects of the overexpressed ErbB2, various ErbB2-blocking strategies have been developed in the laboratories and several have been tested in clinical trials or approved as therapies for ErbB2 overexpressing cancers. In this article, we will discuss the detrimental effects of the erbB2 gene in cancers, with a focus on breast cancer. We will also outline ErbB2-targeting strategies as potential therapies for ErbB2-overexpressing cancers. Progress in understanding the molecular biology of ErbB2 and in molecular-based treatment of ErbB2-overexpressing tumors will bring great benefits to cancer patients.