Semen coagulation is achieved by a series of biochemical processes designed to protect and guide the sperm during its migration through the female genital tract so that spermatozoa reach the ovum successfully. Thus, semen coagulation promotes fertilization. The mechanism of semen coagulation is similar in principle to blood coagulation and fibrinolysis because it requires the catalytic activity of proteases to convert a soluble substrate to an insoluble gel, and then dissolve the gel over a longer period of time. In fact, there are traces of most blood coagulation factors and fibrinolytic factors in semen; the roles of these factors in semen coagulation are still to be determined. This review focuses on two such proteins that have remarkably high levels in semen: protein C inhibitor and tissue factor. Protein C inhibitor is a serine protease inhibitor that modulates the activity of several blood-clotting factors and activated protein C. Tissue factor (thromboplastin) is a membrane protein crucial for the initiation of the extrinsic cascade of blood coagulation. The emerging roles of these two proteins in semen coagulation and in fertilization processes are summarized.