The integrity of the vasculature is compromised under inflammatory conditions, partly as a result of low surface levels of the cell–cell adhesion molecule VE-cadherin. Now Zhu et al. delineate the signalling events that lead to vascular permeabilization following the stimulation of human endothelial cells with interleukin-1β (IL-1β). IL-1β induced NF-κB-independent activation of the GTPase ARF6, which promoted the endocytosis of VE-cadherin. The guanine nucleotide-exchange factor (GEF) ARNO was required for ARF6 activation and co-immunoprecipitated with the IL-1β signalling adaptor molecule MYD88. As the GEF inhibitor SecinH3 reduced vascular permeabilization and tissue inflammation in two models of inflammatory disease, specific targeting of this GEF-dependent arm of IL-1β signalling may be of therapeutic value.