Thrombotic events are a serious and potentially fatal complication during the neonatal period. Despite clinically serious thromboses in up to one percent of neonates and less severe complications (e.g., catheter malfunction secondary to clots) in a much higher percentage, well-designed studies on prevention and treatment of thromboses are lacking. Treatment approaches are largely anecdotal and involve the use of heparin and, occasionally, thrombolytics. Proper monitoring of anticoagulant and thrombolytic effects is difficult because of the limited blood volumes available from neonates and the relatively large sample volumes needed for most coagulation studies. Activated clotting times (ACTs) are preferred because they use low blood volume and are a rapid bedside test. Heparin should be administered with an initial loading dose of 50-100 units/kg followed by a continuous infusion of 20 units/kg/h. Further doses should then be adjusted based on the ACT, targeting a value of 1.5-2.5 times the control. Thrombolytics also have been used in several case reports and are guided by both clinical response and serial D-dimer values. We prefer urokinase 100 units/kg/h for local infusion to the thrombus and urokinase 1000-10,000 units/kg/h for systemic therapy.