This chapter about antithrombotic therapy in neonates and children is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs, and Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading, see Guyatt et al in this supplement, pages 123S–131S). In this chapter, many recommendations are based on extrapolation of adult data, and the reader is referred to the appropriate chapters relating to guidelines for adult populations. Within this chapter, the majority of recommendations are separate for neonates and children, reflecting the significant differences in epidemiology of thrombosis and safety and efficacy of therapy in these two populations. Among the key recommendations in this chapter are the following: In children with first episode of venous thromboembolism (VTE), we recommend anticoagulant therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1B]. Dosing of IV UFH should prolong the activated partial thromboplastin time (aPTT) to a range that corresponds to an anti-factor Xa assay (anti-FXa) level of 0.35 to 0.7 U/mL, whereas LMWH should achieve an anti-FXa level of 0.5 to 1.0 U/mL 4 h after an injection for twice-daily dosing. In neonates with first VTE, we suggest either anticoagulation or supportive care with radiologic monitoring and subsequent anticoagulation if extension of the thrombosis occurs during supportive care (Grade 2C). We recommend against the use of routine systemic thromboprophylaxis for children with central venous lines (Grade 1B). For children with cerebral sinovenous thrombosis (CSVT) without significant intracranial hemorrhage (ICH), we recommend anticoagulation initially with UFH, or LMWH and subsequently with LMWH or vitamin K antagonists (VKAs) for a minimum of 3 months (Grade 1B). For children with non–sickle-cell disease-related acute arterial ischemic stroke (AIS), we recommend UFH or LMWH or aspirin (1 to 5 mg/kg/d) as initial therapy until dissection and embolic causes have been excluded (Grade 1B). For neonates with a first AIS, in the absence of a documented ongoing cardioembolic source, we recommend against anticoagulation or aspirin therapy (Grade 1B).