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Brain metastases (BM) are the most common intracranial tumor in adults. An improved understanding of the genomic architecture of cancers has facilitated a transition from chemotherapy to genotype-guided treatment approaches. Although this shift has translated into improved extracranial disease control and patient outcomes, progression of BM is still a common occurrence. In this review we provide an overview of the current understanding of intermetastatic genomic heterogeneity, summarize the spectrum of genetic alterations detected in BM, and discuss how molecular profiling of BM can create opportunities for refining therapeutic strategies to not only minimize the morbidity from progression of BM but potentially also improve outcomes.