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This chapter focuses on the functions that are encoded by a 40-kb chromosomal region with the features of a pathogenicity island (PAI). The Helicobacter pylori PAI was originally named cytotoxin-associated gene (cag) since it was thought to be associated with expression of the vacuolating toxin (VacA). The module also forms the core of the left and right ends of an insertion sequence common in H. pylori, the IS605 element. One of the most exciting research areas in microbial pathogenesis over the past decade has been the exploration of type III secretion systems. The type IV secretion system can translocate virulence proteins into the host cells. The resulting protrusions on the cell surface (pedestals) somehow resemble the cup-like structures induced by H. pylori, although they are clearly different structures. Recent observations characterized the involvement of the cag PAI in phagocytosis of H. pylori. Mononuclear phagocytes were shown to engulf H. pylori within approximately 4 minutes, but the internalized bacteria were not killed if type I strains were used for the infection. Instead, H. pylori induced homotypic phagosome fusions leading to the formation of large vacuoles. The function of the cag (PAI) in H. pylori-associated disease has been the subject of controversy ever since its discovery in 1993. Clinical studies with different outcomes have been performed to test whether the presence of the cag PAI is connected with peptic ulcer disease or gastric cancer. Future approaches have to consider that the presence of the cagA gene alone is not equal to virulence.