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Regulation of endothelial barrier function is critical for vascular homeostasis, as dynamic and local control of vascular permeability permits macromolecular transport, immune surveillance, and deposition of a fibrin barrier to contain infection at sites of inflammation. Many of the signaling pathways promoting useful vascular permeability, however, are also triggered during disease, resulting in prolonged or uncontrolled vascular leak. Hyperpermeability triggered by inflammation or ischemia in the heart, brain, or lung promotes edema, exacerbates disease progression, and impairs recovery. During cancer, solid tumors release factors that promote the growth of leaky blood vessels which contribute to metastatic spread and limit targeted delivery of anticancer agents.Although the molecular mechanisms governing vascular leak have been studied intensely over the last few decades, recent advances have identified new therapeutic targets that have begun to show preclinical and clinical promise. These approaches have been recently applied with success to an increasing number of disease models.Designing new therapies to limit vascular leak during the progression of disease requires a more complete understanding of the molecular mechanisms governing the endothelial barrier function. This knowledge will benefit the treatment of a growing number of diseases from cardiovascular disease to cancer.