Thrombophilia can be defined in different ways. Broadly, thrombophilia is a term used for several acquired and hereditary conditions that indicate that an individual has a higher-than-normal risk of developing venous thrombosis. It involves multiple risk factors, also outside the blood, that contribute to thrombosis. In a narrow sense, thrombophilia describes a disorder of the blood clotting system that predisposes to thrombosis. This is more tangible and can be determined through laboratory testing. The most common disorders are the factor V Leiden mutation, the prothrombin mutation (20210G>A), antithrombin deficiency, protein C deficiency, protein S deficiency, and the presence of antiphospholipid antibodies. These thrombophilia disorders play a major role in venous thromboembolism and are found in up to 50% of patients with first venous thrombosis. In this chapter, we provide a concise overview encompassing venous thrombosis risk factors, known hereditary and acquired thrombophilia disorders, clinical testing strategies with management implications, and the fascinating territory of new thrombophilia traits and their underlying molecular mechanisms.