The negative regulation of angiogenesis may provide a promising therapeutic target for a number of lifestyle-related diseases, as the switch to an angiogenic phenotype in many tissues represents a critical step during the progression of such disorders. Cartilage is avascular and shows resistance to vascular invasion from the surrounding well-vascularized mesenchyme. Using guanidine extracts of fetal bovine cartilage, we have identified and purified chondromodulin-I (ChM-I) as an angiogenesis inhibitor. The cDNA sequence of this factor has revealed that the ChM-I precursor protein is a type II transmembrane glycoprotein (334 amino acids) and that mature ChM-I is encoded in the C-terminal region of the precursor. After cleavage of the ChM-I precursor at its processing site, mature ChM-I (120 amino acids) is secreted from chondrocytes into the extracellular matrix. Following on from the identification of ChM-I as an angiogenesis inhibitor in cartilage, we have also cloned both mouse and human tenomodulin (TeM), which share significant homology with ChM-I at their C-termini. Moreover, exogenous expression experiments in COS cells suggests that TeM is a type II transmembrane glycoprotein (317 amino acids). When overexpressed in HUVECs, the C-terminal domain (116 amino acids) of the TeM protein shows both anti-angiogenic and anti-tumorigenic activities at equivalent levels to mature ChM-I. In our present review, we discuss the structure, biological activities and localization of these anti-angiogenic molecules.