Gastric cancer in advanced stages lacked effective treatment options. claudin18.2 (CLDN18.2) is a membrane protein that is crucial for close junctions in the differentiated epithelial cells of the gastric mucosa, playing a vital role in barrier function, and can be hardly recognized by immune cells due to its polarity pattern. As the polarity of gastric tumor cells changes, claudin18.2 is exposed on the cell surface, resulting in immune system recognition, and making it an ideal target. In this review, we summarized the expression regulation mechanism of claudin18.2 both in normal cells and malignant tumor cells. Besides, we analyzed the available clinical results and potential areas for future research on claudin18.2-positive gastric cancer and claudin18.2-targeting therapy. In conclusion, claudin18.2 is an ideal target for gastric cancer treatment, and the claudin18.2-targeting therapy has changed the treatment pattern of gastric cancer.