Besides predicting responsiveness to anti-HER2 agents, HER2 aberrations are associated with a high incidence of central nervous system (CNS) metastasis across several cancer types, including breast, lung, gastric and colorectal cancer. In this setting, several novel anti-HER2 agents with relevant CNS activity are emerging, including tucatinib and trastuzumab deruxtecan. Both agents are already FDA-approved for treating advanced breast cancer, but are also being tested for the treatment of other HER2-driven histologies. The confirmation of their activity in other cancer types may provide histology-agnostic weapons against HER2-driven brain metastasis, possibly improving the prognosis of a wide population of cancer patients.