Cancer is a complex disease, in which the microenvironment plays a relevant role. Endothelial cells are an essential component of the tumor microenvironment and their activation to form new blood vessels is a fundamental process to maintain the growth of the primary tumor, for the dissemination of tumor cells to distant organs and for the growth of metastases. The formation of new capillaries, named angiogenesis, is controlled by the balance of positive regulatory factors (inducers of angiogenesis) and negative regulatory factors (inhibitors of angiogenesis) produced by the cells of every tissue of an organism. Our group is focused on the study of the mechanism of action of two inhibitors of angiogenesis: thrombospondin-1 (TSP-1) and pigment epithelium derived factor (PEDF). We use human cellular models and murine tumor models for the study of the mechanism of action of these factors and their antiangiogenic, and antimetastatic potential. We perform angiogenesis assays based on dermal human microvascular endothelial cells and in vivo angiogenesis assays in mice. We complement these approaches with studies in human biopsies of tumors, especially in melanoma. Our research has allowed us to unveiled fundamental aspects of the mechanism of action of TSP-1 and PEDF that support their potential therapeutic application in cancer.