Thrombosis is a multifactorial process. This chapter reviews the coagulation system to provide readers with a general framework from which thrombosis can occur when the balance between procoagulant and anticoagulant pathways is disturbed. Multiple clinical risk factors can predispose patients to develop thrombosis, including hereditary and acquired thrombophilic disorders. This chapter provides an overview of the epidemiology, pathophysiology, testing, and clinical significance of thrombophilia. Prior to undertaking a comprehensive thrombophilia evaluation, it is imperative that the provider consider the patient’s clinical and family history and whether results will impact the management of the thrombotic event.