Gastric cancer is one of the main causes of death by cancer in the world and the infection with Helicobacter pylori is one of the main risk factors associated with its appearance. Helicobacter pylori is a bacterium that colonizes the gastric mucosa, infecting about half of the world´s population. The pathological effects caused by infections with H. pylori greatly depend on an IV type secretion system encoded in the cag pathogenicity island (cagPAI). In this review, we describe the composition of the cagPAI, the alterations of cellular signaling pathways mediated by cagPAI which regulate oncogenic cellular responses that may increase the risk of malignant transformation associated with the infection and the importance of polymorphisms in cagPAI genes as potential markers of progression to gastric cancer.