In this review paper, the salient features of the anticoagulant/fibrinolytic mechanism depending on coagulation protein C, protein S and thrombomodulin are reviewed. Coagulation protein C, activated at the endothelial cell surface in the presence of the complex thrombin/thrombomodulin exerts two anti-thrombotic effects: one anticoagulant dependent on the free protein S and the other pro-fibrinolytic, independent of protein S. Both inherited and acquired deficiencies of protein C and/or protein S lead to a thrombosis-prone state that has to be identified promptly to avoid vaso-occlusive episodes. The experience in Mexico with both the identification and treatment of these deficiencies is reviewed; it is interesting that we have found that patients with autoimmune disorders, mainly systemic lupus erythematosus and primary anti-phospholipid syndrome, have acquired deficiencies of this anticoagulant mechanism that may be related to the thrombogenesis observed in these patients.