Abstract: The vascular network is an integral component of most organs. Beyond assuring an adequate supply of oxygen and nutrients for normal tissue function, vascular structures provide also a critical interface in the balance of tissue homoeostasis and immune functions. Therefore, understanding the biology of the vascular system is a challenging and important objective because it is vital to many physiological and pathological processes. Unravelling mechanisms of blood vessel expansion and remodelling would offer therapeutic options to ameliorate disorders that are currently leading causes of mortality and morbidity, including cardiovascular diseases, cancer, chronic inflammatory disorders, diabetic retinopathy, tissue defects caused by trauma or chronic skin ulcers. This article will review cellular and molecular mechanisms controlling angiogenesis in the light of recent reports and data from our own laboratories. We will focus on the interaction of growth factors with extracellular matrix (ECM) components during the formation of vascular structures in health and disease. Finally, this article will provide a rationale for targeting the ECM–morphogen interplay for therapeutic angiogenesis.