Biomarkers that reliably identify or even predict disease manifestations in systemic lupus erythematosus (SLE) are needed. In a recent issue of the Clinical Journal of the American Society of Nephrology, Wu and colleagues reported on the predictive value of routine D-dimer measurements for future thromboembolic events in patients enrolled in the Ohio SLE study, a unique prospective, longitudinal evaluation of individuals with recurrently active SLE. As in other disease settings, low D-dimer levels (<0.5 microg/ml) excluded clotting at a given time point and identified a zero risk of future clotting events. Conversely, 42% of patients with a high D-dimer level (>2.0 microg/ml) subsequently experienced a clinically relevant clotting event, in some cases in the absence of antiphospholipid antibodies or lupus anticoagulant. This Practice Point commentary considers whether the D-dimer assay will remain simply a tool to rule out thrombosis in symptomatic patients with SLE or whether it could eventually be used to initiate preventive anticoagulation in asymptomatic patients.