It is now appreciated that breast cancer is not a single disease, but instead is a spectrum of tumor subtypes with distinct cellular origins, somatic changes and somewhat predictable clinical behaviors. Gene expression data coming from DNA microarrays, and now sequencing-based technologies, has provided additional insights into the biology of breast cancer that has resulted in the development of a number of clinically useful assays. Our work on breast tumors has led to a new molecular taxonomy that identifies at least five subtypes of breast cancers (Luminal A, Luminal B, HER2-enriched, Basal-like and Claudin-low) and a normal breast-like group. Known as the intrinsic subtypes, these groups have revealed critical differences in incidence, survival, metastatic site specificity, and response to treatment. In addition to the intrinsic subtypes, many other important prognostic and predictive gene expression-based profiles have been identified. These tests have lead to the identification of a subset of ER-positive patients that have an extremely good outcome, and thus, for whom adjuvant endocrine therapy alone appears sufficient. Alternatively, the remaining patients/subtypes including Luminal B, HER2-enriched and Basal-like, show significantly worse prognoses, although targeted therapies for HER2+ patients have greatly improved their outcomes. To address the need for the targeting of Luminal B and Basal-like subtypes, genome sequencing approaches are being employed to provide a means of rationally selecting new targeted agents. Other genomics findings with therapeutic potential include the discovery that a subtype of breast cancer (i.e. the Basal-like subtype) shows significant genetic and mRNA expression similarities with Serous Ovarian Cancers; these similarities include TP53 mutation (>85% with almost no other commonly mutated genes), wide spread genomic instability, RB1-deficiency or Cyclin E1 amplification, BRCA1 inactivation, cMYC amplification, and high expression of AKT3. These common genetic/genomic features suggest that drug regimens that are used for Ovarian Cancer (i.e. a taxane and cis/carboplatin regimen) may also be effective on Basal-like breast cancers, which is being tested at a number of sites worldwide. Data from whole exome sequencing of Basal-like cancers will be presented and used as a model of how genome sequencing can contribute to the identification of potentially targetable driver mutations.