Brain metastasis is an important cause of mortality in patients with cancer and represents the majority of all intracranial tumors. A key step during the metastatic journey of the cancer cell to the brain is the invasion through the blood–brain barrier (BBB). Nevertheless, the molecular mechanisms that govern this process remain unknown. The BBB has been blamed for limiting the access of therapeutic drugs to the brain, which provides a safe haven for cancer cells in the brain and confers poor prognosis for the patient. Here, we explore the genes that control the transmigration of metastatic cancer cells across the BBB, offering new targets for the development of gene and cell therapies against brain metastases.