Intestinal metaplasia of the stomach is a preneoplastic lesion that appears following Helicobacter pylori infection and confers increased risk for gastric cancer development. However, the molecular networks connecting infection to lesion formation and the cellular origin of this lesion remain largely unknown. A more comprehensive understanding of how intestinal metaplasia arises and is maintained will be a major breakthrough towards developing novel therapeutic interventions. Furthermore, after ascertaining the pivotal role of CDX2 in establishing and maintaining intestinal metaplasia, it becomes important to decipher the upstream molecular pathways leading to its ectopic expression. Here, we review the pathophysiology of intestinal metaplasia in the context of the molecular network involved in its establishment and maintenance, with emphasis on CDX2 function and regulation.