Twenty years after the discovery of the vascular endothelial Tie receptor tyrosine kinases and 15 years after the discovery of the Tie2 ligand, angiopoietin-1 (Angpt1, also known as Ang1), a study published in the current issue of the JCI reveals an unexpected loss-of-function phenotype of mice conditionally deleted of the Angpt1 gene. The results suggest that Angpt1 is needed as a vascular stabilizing factor that organizes and limits the angiogenesis response and protects from pathological consequences, such as tissue fibrosis.