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Helicobacter pylori CagA is the first bacterial oncoprotein to be identified in relation to human cancer. CagA is delivered into gastric epithelial cells through a bacterial type IV secretion system and localizes to the plasma membrane, where it undergoes tyrosine phosphorylation by host cell kinases. Membrane-localized CagA then mimics mammalian scaffold proteins and perturbs a number of host signaling pathways in both tyrosine phosphorylation-dependent and -independent manners, thereby promoting transformation of gastric epithelial cells. Helicobacter pylori CagA is noted for structural diversity in its C-terminal region, with which CagA interacts with numerous host cell proteins. This CagA polymorphism is primarily due to differential combination and alignment of the four distinct EPIYA segments and the two different CagA-multimerization sequences in making the C-terminal region. The structural diversity substantially influences the pathophysiological action of CagA. This review focuses on the molecular basis for the structural polymorphism that determines the degrees of virulence and oncogenic potential of individual CagA. The pylogeographic distribution of differential CagA isoforms is also discussed in the context of human migration history, which may underlie large geographical variations in the incidence of gastric cancer in different parts of the world. (Cancer Sci 2011; 102: 36–43)