Warfarin is a well established oral anticoagulant for the treatment of thromboembolic disorders. Warfarin therapy is complicated by a narrow therapeutic index and marked inter-individual dose variability with therapeutic doses ranging from 1 mg to 10 mg/day. Recently genetic variation and resultant drug metabolizing polymorphisms have been found to contribute to warfarin dose variability with resultant hemorrhagic or thromboembolic complications. Cytochrome P4502C9 alters the rate of warfarin metabolism and clearance. A second enzyme, Vitamin K Epoxide Reductase Complex (VKORC) binds and reduces Vitamin K which is necessary for activation of clotting Factors II, VII, IX and X. The VKORC1 gene encodes for Vitamin K Epoxide Reductase Complex subunit 1, a key component of VKORC. The combination of physiologic factors (30%), CYP2C9 variations (20%) and VKORC1 variants (25%) accounts for approximately 75% of warfarin dose variability. This illustrative case report demonstrates the clinical importance of this new information. Clinicians need to incorporate these new genomic findings into appropriate management of warfarin dose anticoagulation.