Low-molecular-weight heparin continues to be recommended as a first-line treatment for patients with venous thromboembolism and active cancer, although there is growing evidence of effectiveness for the use of direct oral anticoagulants in this patient population. The immediate effect of direct oral anticoagulants permits select patients at low risk to initiate treatment in the outpatient setting for venous thromboembolism, including pulmonary embolism. Vitamin K antagonists inhibit the production of vitamin K-related factors and require a minimum of five days overlap with parenteral anticoagulants, whereas direct oral anticoagulants directly inhibit factor II or factor Xa, providing more immediate anticoagulation. Vitamin K antagonists are recommended for patients with mechanical valves and valvular atrial fibrillation. Direct oral anticoagulants are first-line agents for eligible patients for treating venous thromboembolism and preventing stroke in those with nonvalvular atrial fibrillation. Anticoagulation therapy is recommended for preventing, treating, and reducing the recurrence of venous thromboembolism, and preventing stroke in persons with atrial fibrillation.