The oral anticoagulant therapy is used in the prevention and treatment of venous and arterial thromboembolism in many different clinical settings. For this purpose, vitamin K antagonists (VKA), which indirectly reduce the activity of factors II, VII, IX and X preventing the vitamin K-mediated carboxylation of specific glutamic acid residues, and direct oral anticoagulants (DOAC), providing direct inhibition of thrombin (factor IIa) or factor Xa, are available. The VKA monitoring represents a daily challenge for clinical laboratories, due to the increasing number of patients, frequency of needed controls and the management complexity. Several solutions have been proposed to improve the management of patients treated by VKA, such as surveillance in dedicated clinics and use of portable monitors to allow patient self-testing and self-management. Although DOAC have been declared not requiring a standard laboratory monitoring, laboratory testing for measuring drug anticoagulant activity is however needed in many situations, such as in case of bleeding or thromboembolic complications, surgery or invasive procedures, suspected overdose and drug interactions, noncompliance or presence of renal or liver disease.