The study investigates the role of claudin-5 in the blood-brain barrier (BBB) by generating claudin-5-deficient mice. Despite normal brain development and morphology, these mice exhibit a size-selective loosening of the BBB, allowing small molecules (<800 D) but not larger ones to pass through. This finding provides new insights into the molecular physiology of the BBB and suggests a potential method for drug delivery to the central nervous system. The study also highlights the importance of claudin-5 in maintaining the structural integrity and barrier function of tight junctions in brain endothelial cells.The study investigates the role of claudin-5 in the blood-brain barrier (BBB) by generating claudin-5-deficient mice. Despite normal brain development and morphology, these mice exhibit a size-selective loosening of the BBB, allowing small molecules (<800 D) but not larger ones to pass through. This finding provides new insights into the molecular physiology of the BBB and suggests a potential method for drug delivery to the central nervous system. The study also highlights the importance of claudin-5 in maintaining the structural integrity and barrier function of tight junctions in brain endothelial cells.