The extracellular matrix (ECM) is a critical component of stroma-to-cell interactions that subsequently activate intracellular signaling cascades, many of which are associated with tumor invasion and metastasis. The ECM contains a wide range of proteins with multiple functions, including cytokines, cleaved cell-surface receptors, secreted epithelial cell proteins, and structural scaffolding. Fibrillar collagens, abundant in the normal ECM, surround cellular structures and provide structural integrity. However during the initial stages of invasive cancers, the ECM is among the first compartments to be compromised. Also present in the normal ECM is the nonfibrillar collagen XV, which is seen in the basement membrane zone but is lost prior to tumor metastasis in several organs. In contrast, the tumor microenvironment often exhibits increased synthesis of fibrillar collagen I and collagen IV, which are associated with fibrosis. The unique localization of collagen XV and its disappearance prior to tumor invasion suggests a fundamental role in maintaining basement membrane integrity and preventing the migration of tumor cells across this barrier. This review examines the structure of collagen XV, its functional domains, and its involvement in cell-surface receptor-mediated signaling pathways, thus providing further insight into its critical role in the suppression of malignancy.