Development of cancer is associated with activation of blood coagulation. The results of laboratory tests clearly demonstrate that fibrin formation and dissolution is continuously ongoing at different rates in these patients, who are at increased risk of secondary thrombosis. Notably, fibrin formation is also involved in the process of tumor spread and metastasis. The pathogenesis of the hemostatic disorders in cancer is complex and reflects the interaction of different mechanisms involving the activation of various hemostatic components, such as the coagulation and fibrinolytic systems, the vascular endothelium, leukocytes, and platelets. Tumor cells possess the capacity to interact with all of these components. Indeed they directly activate the coagulation cascade by producing their own procoagulant factors, or they can stimulate the prothrombotic properties of other blood cell components. Additional mechanisms of blood clotting activation are started by the initiation of antitumor therapies. In the last 10 years research studies have greatly improved our knowledge of tumor-promoted prothrombotic functions. Understanding the molecular basis of the underlying mechanisms may help to identify better-targeted strategies to prevent thromboembolism in cancer patients. Further, pharmacological modulation of malignant cell hemostatic properties may not only affect the tumor-associated thrombotic risk but may also leave open the possibility to interfere with the progression of the disease.