The extracellular matrix (ECM) plays a crucial role in controlling cell differentiation and function in multicellular animals. It is continually remodelled and synthesised by cells in response to environmental factors such as physical force, hypoxia, trauma and infection. Cells receive survival and positional information from the ECM and it is now evident that ECM biology permeates all aspects of cellular function. Moreover, the ECM is associated with a wide spectrum of common human diseases including arthritis, skeletal deformity, atherosclerosis, diabetes, fibrosis, cancer and poor wound healing. Collagens play a dominant structural role in maintaining the integrity of tissues. However, compelling evidence shows that collagens can also serve as a reservoir for growth factors and modulate cell signaling critical for tissue morphogenesis and homeostasis. Among the 28 collagens described in vertebrates, two are known to be conserved between mammals, fish, flies and worms, namely the basement membrane (BM) collagen IV and a XV/XVIII homologue. A collagen XVIII fragment, endostatin, may have a role in controlling blood vessel formation in tumours as described by Judah Folkman and coworkers. Collagen XVIII is expressed as three N-terminal variant polypeptides, the short, the middle and the long, that arise from the use of two alternative promoters and alternative splicing, whereas collagen XV lacks the N-terminal variants. The long form contains a cysteine-rich frizzled (Fz) domain, which may be involved in Wnt signalling and inhibition of tolloid proteinases. Our data on Col18a1^-/- mice indicate that lack of collagen XVIII delays apoptotic regression of hyaloid vessels. On the other hand, the retinal vessels form poorly, possibly because the heparan sulphate side chains of this collagen are needed to provide VEGF for endothelial cells. Our data thus suggest that collagen XVIII participates both in the inhibition and stimulation of vessel growth. Our recent data also indicates that endostatin can affect formation of lymphatic vessels and metastasis in a squamous cell carcinoma model. Moreover, endostatin fragments appear to counteract in a dominant negative manner the physiological functions of the endostatin domains of the full-length collagen XVIII. Altogether, the distinct roles in physiological and pathological processes of the complex ECM molecule, collagen XVIII, will be discussed.