What we know is little, and what we are ignorant of is immense"; the last words of Laplace still apply to the diagnosis and management of the patent ductus arteriosus (PDA). Despite decades of research, we are searching for the right approach to care for patients with PDA. Nuances of myocardial structural changes and cardiopulmonary interactions with prolonged exposure to excess pulmonary blood flow have played an important role in decision-making. The availability of medical treatments with poor efficacy and, historically, surgical ligation as the only available definitive therapy further widened the gap between observation and definitive closure. As more extremely low birth weight neonates born at earlier gestational ages survive, we are faced with a population whose physiological immaturity and structural alignment of the myocardium predisposes them to myocardial dysfunction and dysregulated vascular tone. Therefore, it may be time to replace historical approaches with a more precise patient-centric therapeutic model. A comprehensive serial echocardiography assessment of the heart function, hemodynamic significance, and clinical context with respect to pulmonary insufficiency and gut perfusion aids the neonatologist in making PDA management decisions. A targeted approach balances risks and benefits of therapy, avoids treatment for infants likely to have early spontaneous closure, and limits prolonged exposure to the pathologic PDA shunt in high-risk infants. There is significant variability in the diagnosis and treatment of the PDA, both within and across centers. This review highlights the clinical obstacles contributing to the variability and illustrates the need for a standardized approach to PDA diagnosis and management.