After the first observations about blood coagulation by Hippocrates, it took until the early 1900s before the classic theory of blood coagulation was presented. As more and more other coagulation factors were discovered, the four-factor coagulation scheme became more complex, but better understood, leading to the current coagulation cascade. As during the last decade it turned out that coagulation factors might do more than just promoting (or inhibiting) blood coagulation, new scientific avenues were pursued focusing on coagulation-independent properties of individual coagulation factors. This led to the current understanding that coagulation factors, like tissue factor (TF), FVII, FX, and thrombin, are important players in inflammation, vascular development, angiogenesis, and tumorigenesis. However, the molecular mechanism by which coagulation factors exert their pleiotropic effects in pathophysiology remains one of the major challenges in the field. This overview presents current insight in how the main coagulation factors might induce inflammation.