Anticoagulation therapy is frequently employed to prevent stroke in patients with atrial fibrillation, prophylaxis of venous thromboembolism and pulmonary embolism in patients with prosthetic heart valves and myocardial infarction, and prevention of pulmonary embolism or deep vein thrombosis after orthopedic surgery or with a history of venous or arterial thromboembolism. Warfarin is an effective anticoagulant that can be prescribed for prolonged periods of time. However, warfarin causes adverse events; if under-dosed, clots may form causing stroke, and if overdosed, life-threatening bleeding may occur. Rivaroxaban and dabigatrin have recently come on the market as warfarin alternatives. While these drugs are reported to produce fewer adverse events, clinical experience suggests otherwise; adverse events do occur. More importantly, there are no reversal agents for these new drugs; managing an anticoagulant induced bleed by one of these agents is difficult. Pharmacogenomic (PG) testing has been applied to warfarin to reveal genetic variants that predict warfarin adverse events. The liver enzyme Cytochrome P450 2C9 metabolizes warfarin. Three variants have been extensively studied; these variants decrease warfarin metabolism predisposing patients to warfarin overdose. The enzyme Vitamin K Epoxide Reductase, known as VKORC1, converts Vitamin K to the reduced form required to activate clotting factors II, VII, IX, and X. Genetic variants in VKORC1 decrease enzyme activity causing warfarin to induce a more profound decrease in activated clotting factors than normal. Patients with this variant are more likely to experience warfarin-induced bleeding. Application of PG testing to large patient populations suggests that modified warfarin dosing based on results of PG reduce warfarin adverse events by more than 35%; this makes warfarin essentially equivalent to rivaroxaban in terms of efficacy. Summing the benefits of 50 plus years clinical experience with warfarin, availability of a reversal agent for warfarin-induced bleeding, and availability of PG testing to guide dosing, warfarin may be the safest anticoagulant on the market today.