Helicobacter pylori (H. pylori) infection causes chronic gastritis and peptic ulceration and is the strongest risk factor for the development of gastric cancer. The pathogenesis of H. pylori is believed to be associated with infection-initiated chronic gastritis, which is characterized by enhanced expression of many inflammatory genes. H. pylori utilizes various virulence factors, targeting different cellular proteins, to modulate the host inflammatory response. In this review, we explore the many different ways by which H. pylori initiates inflammation, leveling many “hits” on the gastric mucosa which can lead to the development of cancer. We also discuss some recent findings in understanding the pathogen-host interactions and the role of transcription factor NF-κB in H. pylori-induced inflammation. J. Cell. Biochem. 114: 491–497, 2013. © 2012 Wiley Periodicals, Inc.