Anti-HER2 therapy has revolutionized the treatment of HER2-positive breast cancer. However, HER2 has emerged as a driver of various other cancers and the indications for HER2-targeted therapy have expanded to include diverse HER2-overexpressing as well as HER2-mutant tumour types beyond breast cancer, facilitated by the advent of novel agents with greater potency and distinct mechanisms of action. Some of these agents have demonstrated promising activity even against HER2-low cancers. Herein, Yoon and Oh describe the landscape of HER2 alterations and HER2-targeted drug development beyond breast cancer. They also discuss new insights into mechanisms of resistance and potential strategies by which they might be overcome.