Fibrin D-dimer, the most commonly used clinical assay for detection of coagulation activation and in vivo fibrin formation and lysis in circulating blood, has been associated with risks of cardiovascular diseases in studies published over the past 15 years. This review discusses, in turn, analytic and preanalytic considerations; associations with risk factors; and associations with coronary heart disease, atrial fibrillation, stroke and cerebrovascular disease, peripheral arterial disease, and venous thromboembolism. These associations suggest that activated coagulation and in vivo fibrin formation and lysis may play a role in arterial, intracardiac, and venous thromboembolism. The potential clinical utility of D-dimer in prediction of cardiovascular risk, in indicating patient groups for prophylactic anticoagulation and in monitoring of anticoagulation, requires further study. Harmonization of results from different assays would increase clinical utility.