Among children, neonates have the highest incidence of thrombosis due to risk factors such as catheter instrumentation, an evolving coagulation system and congenital heart disease. Unfractionated heparin (UFH) is one of the most commonly used anticoagulants in neonates. Published guidelines delineate dosing and monitoring protocols for UFH therapy in newborns. However, challenging clinical situations frequently present that warrants healthcare providers to think critically beyond the range of guidelines, and judiciously resolve specific problems. This review focuses briefly on the epidemiology of neonatal thrombosis and the use of UFH in this population. It is followed by a discussion on dosing of UFH in neonates, limited evidence that forms the basis of published guidelines with justification for a treatment regimen that precludes the use of a heparin loading dose in newborns and monitoring of UFH therapy with currently available tests such as antifactor Xa (anti-Xa) level and activated partial thromboplastin time (APTT). Multiple studies have demonstrated a lack of correlation between anti-Xa levels and APTT as well as between different anti-Xa assays. Many centers world-wide rely only on APTT for monitoring purposes and do not have access to anti-Xa assays. To address these difficulties, we propose two practical algorithms, with and without the use of anti-Xa levels that clinicians can follow when monitoring UFH therapy in neonates. The article concludes with an overview of the side-effects of UFH.