Our understanding of breast cancer as a clinical and biologic entity has been gaining granularity for several decades; in particular, the importance of hormone receptors and HER2 were realized long ago and have served as the impetus for therapeutic agents that have improved the cure rate of estrogen receptor-positive and HER2-positive breast cancer and the lives of thousands of women. The past decade brought even more understanding of the complexity of breast cancer biology through the development and clinical applications of array-based technologies for discovery and prognostication. We now realize that there are at least 5 intrinsic subtypes within breast cancer, at least one of which-the basal-like-currently lacks targeted therapies and is the most pressing therapeutic challenge for the next decade. We have several validated prognostic profiles that allow increased thoughtfulness in adjuvant decision making. With this understanding also comes the recognition that if breast cancer represents several biologically distinct entities, then breast cancer risk assessment and treatment must take this heterogeneity into account, which complicates trial design and interpretation. Despite therapeutic advances and the development of a number of targeted agents against hormone receptor signaling, HER2, and angiogenesis, we have significant challenges to overcome. These include the need for more tissue-based studies to allow us to understand the mechanisms of sensitivity and resistance within and across subtypes, and the need to revisit risk and prevention by subtype.