Pain management in neonates and infants has many unique and important facets, particularly in former preterm infants. Untreated pain and surgical stress in neonates are associated with myriad negative sequelae, including deleterious inflammatory, autonomic, hormonal, metabolic, and neurologic effects. Meanwhile, opioid side effects are also very impactful and affect multiple systems and pathways, particularly in the neonatal and infant population. Regional anesthesia presents a unique opportunity to provide highly effective analgesia; prevent deleterious signaling cascade pathways within the endocrine, immune, and nervous systems from occurring; and create conditions to facilitate reduced reliance on opioids and other analgesics. In some cases, clinicians can completely avoid general anesthesia and systemic anesthetics. This review will discuss some of the unique aspects of pain management in neonates and infants and provide an overview of the different regional anesthetic options available, namely, spinal anesthesia, epidural anesthesia, and peripheral nerve blocks.