Claudin-18.2 (CLDN18.2) is an isoform of a tight junction protein and has emerged as a promising therapeutic target in gastric cancer (GC). CLDN18.2 is responsible for gastric homeostasis and protects epithelial cells from low pH conditions. Interestingly, CLDN18.2 expression is strictly restricted to the stomach, making it an ideal tumor marker. This narrative review presents the characterization and role of claudin 18.2 (CLDN18.2) as a promising biomarker in GC and a target for clinical therapies, more specifically CLDN18.2-targeted drugs and therapies including mABs (e.g., Zolbetuximab, Osemitamab, ZL-1211), bsAB, and CAR-T cell-based immunotherapies. We also summarize numerous ongoing worldwide clinical trials that are evaluating CLDN18.2 as a target for GC treatment. What seems to be crucial is that preclinical and clinical data indicate their high efficacy and safety.