The endothelial angiopoietin (ANG)–TIE growth factor receptor pathway regulates vascular permeability and pathological vascular remodelling during inflammation, tumour angiogenesis and metastasis. Drugs that target the ANG–TIE pathway are in clinical development for oncological and ophthalmological applications. The aim is to complement current vascular endothelial growth factor (VEGF)-based anti-angiogenic therapies in cancer, wet age-related macular degeneration and macular oedema. The unique function of the ANG–TIE pathway in vascular stabilization also renders this pathway an attractive target in sepsis, organ transplantation, atherosclerosis and vascular complications of diabetes. This Review covers key aspects of the function of the ANG–TIE pathway in vascular disease and describes the recent development of novel therapeutics that target this pathway.