Although gastric adenocarcinoma is associated with the presence of Helicobacter pylori in the stomach, only a small fraction of colonized individuals develop this common malignancy. H. pylori strain and host genotypes probably influence the risk of carcinogenesis by differentially affecting host inflammatory responses and epithelial-cell physiology. Understanding the host–microbial interactions that lead to neoplasia will improve cancer-targeted therapeutics and diagnostics, and provide mechanistic insights into other malignancies that arise within the context of microbially initiated inflammatory states.