The clinical guidelines for treating patent ductus arteriosus (PDA) have significantly evolved over the last decades from treating any ductal shunt to more conservative management where only the hemodynamically significant patent ductus arteriosus (HSPDA) is treated. This shift has resulted largely from a lack of evidence from randomized controlled trials supporting a relationship between treating a PDA and improving long-term neonatal outcomes. However, there are many unresolved issues. There is no consensus on the precise definition of HSPDA requiring treatment or a clear understanding of when to treat HSPDA. Moreover, the current evidence shows worsening of the long-term neurodevelopmental outcome for infants undergoing surgical PDA ligation.<br/> The presence of physiologic variability among preterm infants, and the presence of different compensatory mechanisms may make it difficult to establish a link between pathophysiology and long-term outcomes. That is, the physiologic variability cannot be simply assessed by randomly assigning infants into two arms of a study. Relying on research from animal and human studies, this article explains the link between the pathophysiology of a PDA and neonatal outcomes.