Nature Reviews Drug Discovery, Published online: 28 May 2026; doi:10.1038/s41573-026-01450-2 Claudins are emerging as clinically actionable targets in cancer, exemplified by the approval of CLDN-18.2-directed therapy. This review examines the biological basis and therapeutic exploitation of claudins, highlighting diverse targeting modalities and the shift towards leveraging tight junction components as tumour-selective entry points for precision oncology strategies.