More than 150 years ago, Trousseau first suggested a link between cancer and thrombosis. Although this link has been widely described subsequently, the underlying mechanism still remains unclear. Thrombomodulin (TM), a natural endothelial anticoagulant, has proved itself to be an exciting molecule of many functions, not least of those in inflammation, thrombosis, and carcinogenesis. It has been highlighted and supported in many studies as having a cytoprotective role in many types of carcinoma; however, the mechanism of this role remains undefined. It is clear that TM exerts an influence on the endothelium and on the metastatic capacity of cancer, with elevated TM expression conferring a positive predictive and prognostic factor. Exactly how TM features in the metastatic pathway is unclear; however, once this has been clearly outlined, the opportunities afforded by inducers of TM expression may provide potential therapies to improve tumor behavior and impede transendothelial spread of cancer.