Infection with the mucosal resident bacterium Helicobacter pylori can lead to a series of diseases of the gut, culminating in some cases in gastric adenocarcinomas. Still, most long-term H. pylori carriers are apparently unharmed by the bacterium, either because of protective host genetic or environmental effects or because only a subset of H. pylori isolates are virulent. Work in a gerbil model argues for the latter possibility, and Israel et al. use whole genome analysis to examine the genetic differences between 2 strains, B128 and G1.1 that differ in their biological effects. When studied in live animals and in culture, B28 induces consistently stronger effects on epithelial cell death, secretion of the inflammatory cytokine IL-8, and degeneration of the stomach lining. Both strains were known to carry in their genomes a large element called the cag pathogenicity island, where multiple genes are found that influence interactions between the bacterium and the host cell. However, analysis of the 2 strains using an H. pylori chromosome microarray shows that the relatively benign strain, G1.1, carries a large deletion that removes 18 genes from this element. Israel et al. focus on one gene, cagE, and show that disruption of this single gene in a B128 background yields a strain whose effects in culture and in vivo mimic those of G1.1.