Based on animal data, concern has been expressed regarding the potential deleterious neurocognitive effects of general anesthesia during infancy and early life. Although there are no definitive data to prove this effect, the neonatal period has been suggested to be the most vulnerable period. While various inhaled and intravenous anesthetic agents have been implicated, dexmedetomidine and the opioids may be devoid of such effects. However, there are limited data regarding the combination of these agents during neonatal surgery and anesthesia. We present the use of these agents in combination with epidural anesthesia for postoperative analgesia in a 1-day-old neonate during thoracotomy and excision of a congental cystic adenomatoid malformation. Previous reports of the use of this unique combination of agents are reviewed and their role in this scenario discussed.