Large-scale collaborative initiatives using next-generation DNA sequencing and other high-throughput technologies have begun to characterize the genomic landscape of breast cancer. These landmark studies have identified infrequent driver mutations that are potential targets for therapeutic intervention with approved or investigational drug treatments, among other important discoveries. Recently, many institutions have launched molecular screening programs that apply high-throughput genomic technologies to patients with advanced solid malignancies, including breast cancer, to inform clinical decision-making. This article provides an overview of the recent molecular insights in breast cancer, including potentially actionable somatic alterations, the technological platforms currently available in a clinical diagnostics setting to detect these alterations, and ongoing institutional or regional molecular screening programs in advanced breast cancer.