The recent identification of vitamin K epoxid-reductase complex (VKORC1) contributed significantly to our mechanistic understanding of the vitamin K cycle. VKORC1 protein is targeted by Coumarins. Its enzymatic activity represents the rate-limiting step in the vitamin K cycle and gamma-carboxylation of vitamin K dependent proteins. Possibly, VKORC1 is the only component of VKOR activity. Mutations as well as polymorphisms in coding and non-coding regions of the VKORC1 gene have been shown to cause both partial to total coumarin resistance and coumarin sensitivity. Availability of molecular diagnostics (VKORC1, CYP2C9) and laboratory analysis by HPLC (determination of coumarin, vitamin K and vitamin K epoxide levels) is helpful in detection of hereditary and acquired factors influencing coumarin therapy. In the future, these tools might lead to an individualized and safer oral anticoagulation therapy. Furthermore, daily low-dose vitamin K supplementation may improve stability of coumarin-based anticoagulation. In the perspective of the coming new oral anticoagulants, the efficacy and safety profile of the "old" anticoagulants is of major importance. The well established and oeconomic coumarin drugs will benefit from a pharmacogenetic and nutritive adjusted optimization of therapy.