Brain metastases (BM) constitute the majority of intracranial cancers and carry with them a dismal prognosis. Several common cancers have a particular predilection for spread to the brain, amongst them lung cancer, breast cancer, melanoma, renal cell carcinoma (RCC), and more rarely gastrointestinal (GI) cancers. While prognosis has historically been poor and multimodality treatment combining surgery and radiation therapy was the mainstay of treatment, the genomic revolution in cancer therapy is finding increasing applications in treatment of central nervous system (CNS) disease. Targeted therapy, combined with advances in the evaluation of BM for targetable mutations, is showing increased efficacy. Developments in the understanding of brain tropism and targetable signaling pathways in metastasis are elucidating entirely new treatment approaches. This review focuses on advances made in the understanding of the genomics of BM and how this may change the role of targeted therapeutics in this common complication of cancer.