HER2 is an established therapeutic target in a large subset of women with breast cancer; a variety of agents including trastuzumab, pertuzumab, lapatinib, neratinib and trastuzumab emtansine (T-DM1) have been approved for the treatment of HER2-positive breast cancer. HER2 is also overexpressed in subsets of patients with other solid tumours. Notably, the addition of trastuzumab to first-line chemotherapy has improved the overall survival of patients with HER2-positive gastric cancer, and has become the standard-of-care treatment for this group of patients. However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant improvements in the outcomes of patients with HER2-positive gastric cancer. HER2-targeted therapies are also being tested in patients with other solid tumours harbouring HER2 overexpression, and/or amplifications or other mutations of the gene encoding HER2 (ERBB2), including biliary tract, colorectal, non-small-cell lung and bladder cancers. The experience with gastric cancer suggests that the successes observed in HER2-positive breast cancer might not be replicated in these other tumour types, owing to differences in the level of HER2 overexpression and other aspects of disease biology. In this Review, we describe the current role of HER2-targeted therapies beyond breast cancer and also highlight the potential of novel HER2-targeted agents that are currently in clinical development.