Significant progress has been made in neonatal cardiopulmonary bypass (CPB) over the years. At Penn State Health Children’s Hospital, we have established a multidisciplinary research team that brings clinicians, engineers, scientists, research nurses, neuromonitoring technicians, perfusionists, and students from various departments to help reduce adverse outcomes following CPB in neonates. With the help of this team, we evaluate each CPB component in simulated conditions identical to those used in clinical practice. The objective of this review is to demonstrate the results of these translational projects and present critical mistakes to avoid for neonatal CPB patients.