There is now considerable interest in gastrointestinal stromal tumor (GIST) because it can be treated effectively with a targeted molecular agent. The majority of GISTs contain an activating mutation in the KIT protooncogene or, occasionally, in the platelet-derived growth factor-α (PDGFRA) gene. Five years ago, imatinib mesylate, a specific molecular inhibitor of the protein products of these 2 genes, was applied to metastatic GIST. Approximately 80% of patients with metastatic GIST benefit from imatinib, although acquired resistance to the agent may develop. For patients with primary GIST, surgery remains the treatment of choice, and whether outcome is improved by adjuvant imatinib is currently under broad investigation. A combination of imatinib therapy and surgery also may be effective in a subset of patients with metastatic or unresectable primary GIST. In this review, the authors summarize the new multimodality approach to GIST. The integration of surgery and molecular therapy in GIST will serve as a prototype for the management of other solid tumors for which targeted agents become available. Cancer 2005. © 2005 American Cancer Society.