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Persistent pulmonary hypertension of the newborn, or PPHN, represents a challenging condition associated with high morbidity and mortality. Management is complicated by complex pathophysiology and limited neonatal specific evidence-based literature, leading to a lack of universal contemporary clinical guidelines for the care of these patients. To address this need and to provide consistent high-quality clinical care for this challenging population in our neonatal intensive care unit, we sought to develop a comprehensive clinical guideline for the acute stabilization and management of neonates with PPHN. Utilizing cross-disciplinary expertise and incorporating an extensive literature search to guide best practice, we present an approachable, pragmatic, and clinically relevant guide for the bedside management of acute PPHN. KEY POINTS: · PPHN is associated with several unique diagnoses; the associated pathophysiology is different for each unique diagnosis.. · PPHN is a challenging, dynamic, and labile process for which optimal care requires frequent reassessment.. · Key management goals are adequate tissue oxygen delivery, avoiding harm.., Competing Interests: O.F. reports payment or honoraria from the University of Florida, Jacksonville Honorarium for Pediatric Grand Rounds presented at UF Jacksonville in January 2020, “Building & Implementing a Small Baby Program.” O.F. reports support from Atom Medical (Tokyo, Japan) for travel and lodging to visit NICUs in Japan in October 2019 and collaborate on the care of extremely preterm infants. M.K.B. reports monetary support for travel/meeting attendance for NeoHeart 2019, to present as conference faculty. M.K.B. reports leadership or fiduciary role for Neonatal Cardiac Special Interest Group, Children's Hospital Neonatal Consortium., (Thieme. All rights reserved.)