Unfractionated heparin is frequently used in tertiary pediatric centers for the prophylaxis and treatment of thromboembolic disease. Recent evidence suggests that the clinical outcomes of unfractionated heparin therapy in children are poor, as determined by target-range achievement and adverse-event rates. These reports of poor outcomes may be related to an age-dependent mechanism of action of unfractionated heparin. Furthermore, several published studies have indicated that unfractionated heparin–monitoring assays currently in clinical use have significant limitations that likely affect the safety and efficacy of anticoagulant management. This review summarizes the growing body of evidence suggesting that pediatric-specific recommendations for unfractionated heparin therapy management are required to improve clinical outcomes related to this commonly prescribed medication.