It is increasingly recognized that the abnormal physiologic consequences of pulmonary hypertension (PH) may contribute to poor cardiopulmonary health in premature babies. Conflicting literature has led to clinical uncertainty, pathological misinterpretation, and variability in treatment approaches among practitioners. There are several disorders with overlapping and interrelated presentations, and other disorders with a similar clinical phenotype but diverse pathophysiological contributors. In this review, we provide a diagnostic approach for acute hypoxemic respiratory failure in the preterm neonate, outline the pathophysiological conditions that may present as acute PH, and discuss the implications of high pulmonary vascular resistance (PVR) on the cardiovascular system. Although PVR and respiratory management are highly interrelated, there may be a population of preterm neonates in whom inhaled nitric oxide may improve illness severity and may relate to outcomes. A management approach based on physiology that considers common clinical conundrums is provided. A more comprehensive understanding of the physiology may help in informed decision-making in clinical situations where conclusive scientific evidence is lacking. Regardless, high-quality research is required, and appropriate definition of the target population is paramount. A thoughtful approach to cardiovascular therapy may also provide an avenue to improve neurodevelopmental outcomes while awaiting more clear answers.