Gastric and gastroesophageal adenocarcinomas are aggressive malignancies despite current standard-of-care treatments. For patients whose tumors express human epidermal growth factor receptor 2 (HER2), HER2-targeted treatments have been shown to improve outcomes. This review summarizes key trials that have guided contemporary use of these agents in both the localized and advanced settings. It also discusses limitations to current approaches in testing HER2 status and methods to better identify good candidates for these treatments. Finally, the review highlights notable ongoing studies investigating novel combinations and HER2-directed agents.