Vascular leakage is a characteristic of critical illnesses such as septic shock and acute respiratory distress syndrome. It results in hypotension and tissue edema and contributes to organ dysfunction. It has long been taught that increased vascular permeability is a natural consequence of inflammation; in particular, many clinicians believe that it occurs inevitably during leukocyte recruitment to a site of infection. In fact, abundant research now indicates that vascular leakage and leukocyte emigration do not necessarily occur together in a blood vessel. The molecular mechanisms underpinning these processes—allowing leukocytes to exit the circulation without increasing vascular permeability—are starting to be elucidated and establish vascular leakage as a viable therapeutic target. Several preclinical studies indicate that vascular leakage can be reduced without impairing cytokine production, leukocyte recruitment, and pathogen clearance. The realization that leukocyte traffic and vascular permeability can be regulated separately should spur development of therapies that decrease vascular leakage and tissue edema without compromising the immune response.