Hemostasis is a sophisticated sequence of events aimed to repair vessel injury. This process occurs in combination with angiogenesis, which leads to new blood vessel formation helping in the wound repair and facilitating tissue healing. The fine mechanisms that regulate hemostasis and angiogenesis are well described, but for long time, coagulation factors (CFs) have been considered merely players in the coagulation cascade. However, several experimental evidences highlight the crucial functions of these CFs in regulating endothelial functionality, especially in the angiogenic process. Some of these CFs (e.g. thrombin and tissue factor) have been widely investigated and have been described to trigger intracellular signaling related to endothelial cell (EC) functionality. For others (e.g. factor VIII and thrombomodulin), potential receptors and molecular mechanisms have not been fully elucidated but some data show their potential to induce EC response. This review focuses on the emerging roles of selected CFs in regulating EC functions, especially highlighting their ability to activate signaling pathways involved in the angiogenesis, migration, proliferation and endothelial barrier stability.