The prognosis and quality of life of patients with breast cancer brain metastases is generally poor and there is no effective treatment. A generally applicable computational model integrated with systems biology experiments was developed and applied to reposition existing drugs that would inhibit brain metastases. Ten repositioned drug candidates with potential brain permeability were identified. In xenograft models, sunitinib (approved for treating advanced renal cell carcinoma and gastrointestinal stromal tumors) and dasatinib (approved for treating chronic myelogenous leukemia) were repositioned to prevent metastatic outgrowth of breast cancer cells in the brain. For details, see article by Zhao and colleagues on page 6149.