Venous thromboembolism (VTE) is an important but historically under-recognized problem in pediatrics, with an incidence concentrated in hospitalized children. A number of specific VTE diseases with discrete triggers have been described, but the most common pediatric trigger is the presence of central venous access devices. VTE diseases, though heterogenous in etiology, are linked by the common therapeutic strategies shared by their management. Historically, the most commonly used drug therapies have been unfractionated heparin, low-molecular-weight heparins, and vitamin K antagonists, based on extrapolation from adult data rather than any specific pediatric trials. Although these widely used drugs appear safe and effective in expert hands, the historical lack of pediatric data is problematic in view of the recognized significant differences between children and adults with regards to hemostatic physiology, VTE etiology, and drug pharmacokinetics. The increasing adult usage of novel VTE pharmacotherapies such as direct oral anticoagulants (DOACs) has led to considerable interest in exploring the pediatric applications of these newer drugs. This review summarizes the advantages and disadvantages of existing VTE pharmacotherapies and outlines emerging novel pediatric VTE therapies, particularly DOACs, within the context of the current pediatric trial landscape.