Despite advances made in technology and neonatal intensive care, the rate of hemorrhagic and thrombotic complications remains unacceptably high in patients undergoing extracorporeal membrane oxygenation (ECMO) and these complications negatively impact morbidity and mortality. Management of anticoagulation in neonates who have a developing hemostatic system is vastly different from adults and poses unique challenges. Variation in practice among ECMO centers regarding anticoagulation monitoring and titration reflects the lack of high-quality evidence. Novel anticoagulants may offer alternative options, though their impact on outcomes is yet to be demonstrated. In this chapter, we review the hemostatic alterations that occur during ECMO with a focus on current approaches and limitations to anticoagulation titration in neonates on ECMO.