Microsatellite instability (MSI) is a common feature of gastric cancers that reflects underlying mismatch-repair deficiency in the tumor, caused most frequently by methylation of the hMLH1 promoter. Tumors with MSI have been found to inactivate certain target genes by permitting an increased frequency of mutations in mononucleotide runs in their coding regions. Gastric tumors with MSI have a distinct clinicopathological profile with a relatively good prognosis. Using the simple and robust methodologies available, MSI detection in gastrointestinal tumors promises to be one of the first widely used molecular prognostic tests for human cancer. Here, we review the molecular context of this exciting prospect with respect to one of the world's most prevalent cancers, that of the stomach.