Activation of receptor tyrosine kinases requires ligand binding. Tao et al. propose that, in the case of a receptor for vascular endothelial growth factor (VEGF) called the kinase insert domain receptor (KDR), a structural feature in the receptor's ectodomain ensures that this is the case. When mutant receptors lacking certain extracellular immunoglobulin-like domains were expressed in endothelial cells, receptor activation and stimulation of downstream signaling events were observed in the absence of ligand. These mutants were still able to bind to ligand, although they did not require this interaction. The authors propose that in the absence of VEGF, the threedimensional structure does not allow the juxtaposition of the catalytic domains between KDR monomers that facilitates transphosphorylation. VEGF binding could cause a conformational change in the monomers that would relieve this structural constraint and allow receptor dimerization. This may be a general strategy for receptors to prevent aberrant, ligand-independent signaling.