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ABSTRACT: Vascular Endothelial Growth Factors (VEGF)-C and VEGF-D are angiogenic and lymphangiogenic members of the VEGF family. These two growth factors form a subgroup by virtue of their structural and functional similarities. VEGF-C and VEGF-Dare ligands for VEGF receptors, VEGFR-2 and VEGFR-3 and signalling via VEGFR-3 is important for the development of the vascular system and maintenance and function of the lymphatic system. Differential cell surface antigen expression by blood vascular and lymphatic endothelial cells has provided a method of isolating lymphatic endothelial cells for further investigation of the roles of VEGF-C and VEGF-D. Novel tumor and lymphedema models have been constructed to analyze the in vivo functions of VEGF-C, VEGF-D and VEGFR-3. Although proliferating lymphatic endothelial cells have been identified in human tumors, the role of lymphatic vessel density and its relationship to the expression of lymphangiogenic growth factors has yet to be clarified fully. The expression of VEGF-C and VEGF-D in human tumors is associated with negative clinicopathological variables, but some conflicting results are found which may be explained by differences in methodology, tumor biology and microenvironmental influences. Evaluation of the therapeutic potential of manipulation of the VEGF-C/D signalling pathway requires further clarification of the functions of the growth factors in health and disease.