Neonatal abstinence syndrome (NAS) from in utero opioid exposure has reached epidemic levels in the United States. Although nonpharmacologic therapies form the foundation of care, many neonates require pharmacotherapy. Morphine represents the most widely used first-line agent and effectively treats the symptoms of withdrawal. However, methadone or buprenorphine may facilitate earlier discharge. Although phenobarbital is traditionally used when opioids fail, clonidine may be a more appropriate adjunctive agent to minimize negative neurodevelopmental impact. Consideration of the available data allows hospitals to generate effective pharmacologic strategies to manage NAS while further research continues.