The most virulent strains of Helicobacter pylori carry a genomic island (cagPAI) containing a set of 27-31 genes. The encoded proteins assemble a syringe-like apparatus to inject the cytotoxin-associated gene A (CagA) protein into gastric cells. This molecular device belongs to the type IV secretion system (T4SS) family albeit with unique characteristics. The cagPAI-encoded T4SS and its effector protein CagA have an intricate relationship with the host cell, with multiple interactions that only start to be deciphered from a structural point of view. On the one hand, the major roles of the interactions between CagL and CagA (and perhaps CagI and CagY) and host cell factors are to facilitate H. pylori adhesion and to mediate the injection of the CagA oncoprotein. On the other hand, CagA interactions with host cell partners interfere with cellular pathways to subvert cell defences and to promote H. pylori infection. Although a clear mechanism for CagA translocation is still lacking, the structural definition of CagA and CagL domains involved in interactions with signalling proteins are progressively coming to light. In this chapter, we will focus on the structural aspects of Cag protein interactions with host cell molecules, critical molecular events precluding H. pylori-mediated gastric cancer development.