Metastatic breast cancer (mBC) remains responsible for the majority of breast cancer deaths. Whereas clinical outcomes have improved with the development of novel therapies, resistance almost inevitably develops, indicating the need for novel therapeutic approaches for the treatment of mBC. Recent investigations into mBC genomic alterations have revealed novel and potential therapeutic targets. Most notably, therapies against PIK3CA mutation and germline BRCA1/2 mutations have solidified the role of targeted therapy in mBC, with treatments against these alterations now approved by the U.S. Food and Drug Administration (FDA) on the basis of clinical benefit for patients with mBC. Familiarity with relevant genomic alterations in mBC, technologies for mutation detection, methods of interpreting genomic alterations, and an understanding of their clinical impact will aid practicing clinicians in the treatment of mBC as the field of breast oncology moves toward the era of precision medicine.