Factor V Leiden is the most prevalent genetic thrombophilia in people of European descent. Since its discovery, much clinical information has been gathered regarding the distribution and prevalence of the genetic mutation, the mechanism of thrombophilia, and its association with clinical thromboembolic events. Although its association with venous thromboembolism is clear, the role of Factor V Leiden in other disease states is not clear. A review of the literature regarding the mechanism of hypercoagulability, genetic versus functional diagnostic tests, screening issues, relationship to arterial thromboses, pregnancy and pregnancy complications, and treatment are discussed.