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The decrease of endothelial barrier function is central to the long-term inflammatory response. A pathological alteration of the ability of en-dothelial cells to modulate the passage of cells and solutes across the vessel underlies the development of inflammatory diseases such as atherosclerosis and multiple sclerosis. The inflammatory cytokine tu-mour necrosis factor (TNF) mediates changes in the barrier properties of the endothelium. TNF activates different Rho GTPases, increases filamentous actin and remodels endothelial cell morphology. How-ever, inhibition of actin-mediated remodelling is insufficient to prevent endothelial barrier disruption in response to TNF, suggesting that addi-tional molecular mechanisms are involved. Here we discuss, first, the pivotal role of Rac-mediated generation of reactive oxygen species (ROS) to regulate the integrity of endothelial cell-cell junctions and, second, the ability of endothelial adhesion receptors such as ICAM-1, VCAM-1 and PECAM-1, involved in leukocyte transendothelial mi-gration, to control endothelial permeability to small molecules, often through ROS generation. These adhesion receptors regulate endothe-lial barrier function in ways both dependent on and independent of their engagement by immune cells, and orchestrate the crosstalk be-tween leukocyte transendothelial migration and endothelial permea-bility during inflammation