Gastric cancer is the third most common cause of cancer-related death. Although the incidence of gastric cancer in the United States is relatively low, it remains significantly higher in some countries, including Japan and Korea. Interactions between cancer stem cells and the tumor microenvironment can have a substantial impact on tumor characteristics and contribute to heterogeneity. The mechanisms responsible for maintaining malignant cancer stem cells within the tumor microenvironment in human gastric cancer are largely unknown. Tumor cell and genetic heterogeneity contribute to either de novo intrinsic or the therapy-induced emergence of drug-resistant clones and eventual tumor recurrence. Although chemotherapy often is capable of inducing cell death in tumors, many cancer patients experience recurrence because of failure to effectively target the cancer stem cells, which are believed to be key tumor-initiating cells. Among the population of stem cells within the stomach that may be targeted during chronic Helicobacter pylori infection and altered into tumor-initiating cells are those cells marked by the cluster-of-differentiation (CD)44 cell surface receptor. CD44 variable isoforms (CD44v) have been implicated as key players in malignant transformation whereby their expression is highly restricted and specific, unlike the canonical CD44 standard isoform. Overall, CD44v, in particular CD44v9, are believed to mark the gastric cancer cells that contribute to increased resistance for chemotherapy- or radiation-induced cell death. This review focuses on the following: the alteration of the gastric stem cell during bacterial infection, and the role of CD44v in the initiation, maintenance, and growth of tumors associated with gastric cancer. Keywords: Helicobacter pylori, CD44v9, CD44v6, Inflammation