The number of treatment options available to patients with breast cancer is larger and more complex than ever before. This is due in part to increased understanding of breast cancer tumor biology and the signaling pathways involved in tumor development and progression, which drives new areas of breast cancer research and the development of novel agents. Therapies targeting HER2 signaling, angiogenesis, DNA repair, and many other essential cellular processes that are dysregulated in cancer have produced significant improvements in disease outcome, although careful patient selection and toxicity management are required to maximize their therapeutic potential. Multigene assays have added to the ability to predict disease outcome and degree of response to adjuvant chemotherapy, but the application of these assays in the right clinical context is necessary. Unfortunately, despite the use of appropriate and effective local and adjuvant therapies, some patients with early-stage breast cancer will eventually develop metastatic disease. Most of these patients will have received standard therapies in the adjuvant setting and/or will develop resistance to these therapies at some point during treatment. Thus, implementation of novel strategies is necessary to overcome resistance and improve disease outcome. This in turn will require creative clinical trial designs, more efficient accrual, and rapid translation of results into the clinical setting. This summary highlights selected challenges in the current management of breast cancer and discusses expert perspectives, key questions, areas of debate, and future directions.