Activated protein C resistance, most often caused by a single point mutation in the factor V gene, is the most common hereditary coagulation abnormality associated with venous thrombosis. Recent studies have established risk estimates of thrombosis in multiple clinical settings. The impact of activated protein C resistance on the absolute thrombotic risk of a given individual is significantly influenced by the presence or absence of other acquired or congenital risk factors. In this paper, the complex interplay between different risk factors for venous thrombosis is discussed. Additionally, the potential significance for arterial thrombosis of activated protein C resistance, that is not due to the genetic variant, Glutamine 506 factor V, is discussed.