<p>Epithelial-derived malignancies account for the majority of human tumours and present considerable treatment challenges owing to their heterogeneity, metastatic potential and resistance to therapy. The claudin family of tetra-transmembrane proteins was identified approximately 28 years ago as containing key regulators of epithelial function. These proteins are integral components of tight junctions, which control barrier integrity, selective channel permeability and cellular organization in epithelial tissues. Subsequent murine studies revealed that claudins also have tissue-specific physiological roles, whereas clinical studies demonstrated that their expression is frequently dysregulated in various cancers, highlighting their potential as therapeutic targets. In the past few decades, increasing efforts to exploit claudins in cancer therapy have led to the development of targeted molecules, including zolbetuximab, a first-in-class CLDN-18.2-targeted antibody for the treatment of gastric cancer, which has been recently approved by the United States Food and Drug Administration. This milestone emphasizes the therapeutic potential of targeting this protein family and its possible role in expanding treatment options for cancer. In this review, we discuss the evolving landscape of claudin-targeting therapeutics, examining key advances, emerging challenges and future prospects.</p>