The reason why some individuals remain Helicobacter pylori infected for life but without any symptoms while others develop severe diseases is only partially clarified. Presumably, it depends on multifactorial interactions among host immunologic and physiologic factors, bacterial virulence determinants, and environmental influences modulating the host response. Much effort has been made to identify host genetic factors that may explain an individual susceptibility of the host to H. pylori infection. The identification of H. pylori determinants and the elucidation of their role in modifying the host immune responses were further delineated. The ability of H. pylori to overcome the defense mechanisms on mucosal surfaces as well as to modulate the immune response by interfering with host recognition and transduction systems has been shown. Also new bacterial anti-inflammatory defense systems have been described. Findings in experimental animal models and humans with natural H. pylori infection suggested a double role of regulatory T cells in the course of H. pylori infection: protecting the infected host against excessive gastric inflammation and, in contrast, promoting bacterial colonization.