Heart valve prostheses carry a risk for thrombosis and require an antithrombotic strategy to prevent stroke, systemic embolism, and prosthetic valve thrombosis. Contemporary randomized trials to guide the clinician on the optimal anticoagulant treatment are scarce, and the validity of the historical data for current recommendations can be questioned in view of the changes in valve prostheses, the patient population, and antithrombotic therapies. This limited evidence from clinical trials translates into divergent recommendations from the different scientific societies on the optimal intensity of oral anticoagulation and on the indication for antiplatelet therapy. The availability of new antithrombotic agents and the unclear thrombotic risk of the currently used prostheses underscore the need to redefine antithrombotic treatment in patients with heart valve prostheses.