Venous thromboembolism (VTE) is a frequent and life-threatening complication in patients with cancer. The underlying mechanisms of cancer-associated VTE are still not completely understood. However, emerging studies indicate that the mechanisms differ across tumor types. A recent study revealed that in patients with brain tumors, podoplanin overexpression is strongly correlated with intratumoral thrombotic vessels, hypercoagulability and increased VTE risk. In vitro experiments demonstrated that platelet aggregation induced by human glioblastoma cells was highly podoplanin-dependent. Podoplanin is a transmembrane glycoprotein with the ability to induce platelet activation via the platelet-receptor CLEC-2. Moreover, podoplanin is a lymphatic endothelial marker and exhibits substantial functions during embryonic development. It is variously upregulated by many cancers including primary brain tumors and linked to malignant progression and poor survival. In vivo studies have indicated that the podoplanin-CLEC-2 axis might be mechanistically involved in the development of venous thrombosis. In this review, we discuss the role of podoplanin in promoting cancer-associated VTE. Since podoplanin is associated with VTE risk in brain tumor patients, it could be a useful biomarker to identify patients at very high VTE risk. Those patients may benefit from primary thromboprophylaxis. In addition, the podoplanin-CLEC-2 axis might serve as an attractive target for new therapies against cancer-associated VTE.