Tight junction proteins of the blood–brain barrier are vital for maintaining integrity of endothelial cells lining brain blood vessels. The presence of these protein complexes in the space between endothelial cells creates a dynamic, highly regulated and restrictive microenvironment that is vital for neural homeostasis. By limiting paracellular diffusion of material between blood and brain, tight junction proteins provide a protective barrier preventing the passage of unwanted and potentially damaging material. Simultaneously, this protective barrier hinders the therapeutic effectiveness of central nervous system acting drugs with over 95% of small molecule therapeutics unable to bypass the blood–brain barrier. At the blood–brain barrier, claudin-5 is the most enriched tight junction protein and its dysfunction has been implicated in neurodegenerative disorders such as Alzheimer’s disease, neuroinflammatory disorders such as multiple sclerosis as well as psychiatric disorders including depression and schizophrenia. By regulating levels of claudin-5, it is possible to abrogate disease symptoms in many of these disorders. This review will give an overview of the blood–brain barrier and the role of tight junction complexes in maintaining blood–brain barrier integrity before focusing on the role of claudin-5 and its regulation in homeostatic and pathological conditions. We will also summarise therapeutic strategies to restore integrity of cerebral vessels by targeting tight junction protein complexes.