It is clear that mismatch repair protein deficient/microsatellite instability high (MSI-H) esophagogastric adenocarcinoma has a distinct biology from proficient/microsatellite stable (MSS) disease. The emerging data in MSI-H cancers present exciting opportunities to advance treatment but also raise challenges about the optimal treatment of these patients. Disease specific treatment approaches for MSI-H cancers inevitably will lead to divergence away from the conventional treatment paradigms of MSS disease.