Helicobacter pylori plays an important role in the development of atrophic gastritis that represents the most recognized pathway in multistep gastric carcinogenesis. Recent studies suggest that a combination of host genetic factors, bacterial virulence factors, and environmental and lifestyle factors determine the severity of gastric damage and the eventual clinical outcome of Helicobacter pylori infection. As to bacterial virulence factors, a high proportion of Japanese strains are cagA+vacAs1. The CagA protein is injected from attached Helicobacter pylori into gastric epithelial cells and the CagA-SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. Host cytokine gene polymorphisms and a frequent single nucleotide polymorphism in the PTPN11 gene that encodes SHP-2 may associate with gastric atrophy among Helicobacter pylori-infected subjects. Prevention of gastric cancer requires the development of better screening strategies for determining eradication candidates and further improvement of treatments of Helicobacter pylori infection.