Although gastric cancer has been investigated for centuries, the association with Helicobacter pylori infection has been recognized for only the past few decades. Although the disease has been declining in most industrialized countries, it remains the second most common cause of cancer death worldwide and is, in theory, a largely preventable disease. We have gained many new insights and advances from studies of Helicobacter-infected mouse models. These models corroborate findings in human patients, in whom disease outcome is largely determined by the expression of host proinflammatory cytokines. Studies of the cellular origins of cancer in the Helicobacter-infected mouse model has led to the surprising insight that gastric cancer may originate from circulating bone marrow-derived stem cells (BMDC) and not from resident tissue stem cells as previously believed. It is likely that this new BMDC paradigm of epithelial cancer will prove useful in future investigations of gastrointestinal metaplasia and gastrointestinal cancers associated with chronic inflammation.