Twenty-five years after the publication of seminal studies showing that HER2 gene amplification and protein overexpression are oncogenic in breast cancer, Bose and colleagues report on the identification of activating HER2 somatic mutations that, albeit rare, may determine the response of breast cancer cells to anti-HER2 agents. These results herald a new era for the potential use of existing HER2-targeted agents for the treatment of patients with HER2-mutant breast cancer.