To elucidate the mechanistic-basis for the lack of clinical activity of older HER2-targeted therapies in patients with urothelial cancer and to guide the clinical development of novel HER2-targeted therapies including HER2-targeted ADCs, we performed integrated molecular and clinical analyses of patients with urothelial cancer enrolled on a prospective molecular tumor profiling initiative. The gene discussed is ERBB2; the disease is neoplasm.