Atherothrombosis, characterised by atherosclerotic lesion disruption with superimposed thrombus formation, is the major cause of acute coronary syndromes (ACS) and cardiovascular death. It is the leading cause of mortality in the industrialised world. Atherosclerosis is a diffuse process that starts early in childhood and progresses asymptomatically through adult life. Later in life, it is clinically manifested as coronary artery disease, stroke, transient ischaemic attack, and peripheral arterial disease. From the clinical point of view, we should envision this disease as a single pathologic entity that affects different vascular territories. Available antithrombotic therapy is very safe and efficient but the morbidity and mortality due to atherothrombosis is still unacceptably high. Recent evidence suggests that inhibition of tissue factor or elements in the tissue factor pathway (i.e., factors VIIa and Xa, or thrombin) has the potential to further improve outcomes in atherothrombosis. Here, we will review the most important concepts and advances in the pathogenesis, prevention, and antithrombotic treatment of this widespread disease.