Factor V Leiden (FVL) is the most common known inherited cause of thrombophilia; it is present in approximately 5% of the Caucasian population. Although the risk of venous thrombosis associated with this polymorphism in various medical settings is well described, its effect on perioperative risk is only beginning to be explored. Specifically, there are few studies addressing the potential risks of FVL in the surgical population, in which both hemorrhagic and thrombotic complications convey substantial clinical and economic significance. There are speculations and unproven hypotheses regarding FVL in this population, and these therefore highlight the need to comprehensively address this issue. This review will describe the physiology of the FVL mutation, briefly clarify its risk in the nonsurgical setting, and assess current data regarding FVL in noncardiac and cardiac surgery. Finally, a summary of current clinical evidence and a plan for more detailed investigation of this potentially significant risk factor will be proposed.