Chronic inflammation underlies many human diseases including cancer. The magnitude and direction of the inflammatory response is often directed by host genetic factors interacting with environmental exposures. Quite often, the environmental trigger is a microbial agent and the host's genetically determined response is crucial in setting the right tone for handling this threat. An inadequate response runs the risk of allowing the infection to become permanently established causing chronic damage, while too vigorous a response might cause collateral damage to the host's essential physiological pathways. Helicobacter pylori-induced gastric cancer is a paradigm for microbially induced and chronic inflammation-driven malignancy. In this review, we summarise current knowledge about the role of host genetic factors in the pathogenesis of this malignancy. The review illustrates the basic principles of genetic epidemiology and host-bacterial interactions and offers an example of how basic knowledge of the pathophysiology of a disease directed the search for the relevant host genetic factors. This contrasts with current approaches, driven by advanced technology, where genetic risk factors are being identified first with the hope that these will shed light on the pathogenesis of disease. Both approaches are necessary to make advances in reducing disease burden in society.