During limb morphogenesis, developing digits are initially interconnected by soft tissue but then become separated as this tissue undergoes programmed cell death (PCD) and regresses. Now, Elazar Zelzer and co-workers demonstrate that vascular patterning in the mouse limb regulates interdigital cell death by a reactive oxygen species (ROS)-dependent mechanism (p. 672). They demonstrate the presence of a complex and high-density capillary network within interdigital regions at the onset of PCD; by contrast, the developing digits are unvascularized. As PCD progresses, they report, the vasculature concomitantly becomes remodelled. They further show that a decrease in interdigital blood vessel numbers, induced by inactivating VEGF in the limb mesenchyme, inhibits PCD. By contrast, hypervascularization following VEGF overexpression in the limb leads to elevated PCD and an expansion of the domain in which PCD occurs. Finally, the researchers demonstrate that interdigital PCD is dependent on oxygen and the production of ROS. Together, these findings highlight a novel function for vascular patterning, and suggest the existence of a mechanism by which vascularization of interdigital regions leads to an increase in tissue oxygenation, which in turn triggers ROS production and PCD.