In the last decade, much data has been generated concerning the molecular mechanisms of lymphangiogenesis and its significance in pathological conditions. This was mainly due to the discovery of lymphatic endothelial cell (LEC)-specific markers, such as vascular endothelial growth factor receptor-3 (VEGFR-3), LYVE-1, Prox-1 and podoplanin. Podoplanin, originally detected on the surface of podocytes, belongs to the family of type-1 transmembrane sialomucin-like glycoproteins. Although specific for lymphatic vascular (LV) endothelium, podoplanin is expressed in a wide variety of normal and tumor cells. The expression of podoplanin is induced by the homeobox gene Prox-1 and a specific endogenous receptor was identified on platelets. Immunohistochemical detection of podoplanin/D2-40 in LECs was used in many studies to evaluate the LV microvascular density (LVMD) in peritumoral and tumoral areas, and to correlate LVMD with lymph node status and prognosis. Podoplanin significantly increases the detection of lymphovascular invasion in different types of malignant tumors. Podoplanin expression was found in tumor cells of various types of cancer, such as vascular tumors, malignant mesothelioma, tumors of the central nervous system (CNS), germ cell tumors and squamous cell carcinomas. This expression in tumor cells is useful for pathological diagnosis and podoplanin seems to be expressed by aggressive tumors, with higher invasive and metastatic potential. Based on these data, podoplanin might be considered as an attractive therapeutic target for both LVs and tumor cells. Further studies are necessary to investigate differences in the expression of podoplanin in normal and tumor-associated lymphatics, and between the expression of podoplanin in normal non-LECs and tumor cells.