Highlights - A hypercoagulable state established within the tumor accounts for the frequent hemostatic complications that occur in cancer patients, including venous thromboembolism. - The coagulation cascades exert multiple direct and indirect effects on cancer cells and the components of the tumor microenvironment, both within and outside of the vascular space. - The recent application of systems biology and single-cell approaches provides a comprehensive and deeper view of the coagulome and highlights its link to the tumor microenvironment. - The study of the coagulome provides unprecedented opportunities to explore the tumor microenvironment, to better predict the hemostatic complications, revisit the significance of clinical biomarkers, and it might ultimately enable us to steer the tumor immune response or vascular integrity. Human tumors often trigger a hypercoagulable state that promotes hemostatic complications, including venous thromboembolism. The recent application of systems biology to the study of the coagulome highlighted its link to shaping the tumor microenvironment (TME), both within and outside of the vascular space. Addressing this link provides the opportunity to revisit the significance of biomarkers of hemostasis and assess the communication between vasculature and tumor parenchyma, an important topic considering the advent of immune checkpoint inhibitors and vascular normalization strategies. Understanding how the coagulome and TME influence each other offers exciting new prospects for predicting hemostatic complications and boosting the effectiveness of cancer treatment.