OBJECTIVE This review will discuss the complex nature of maternal and other factors that can affect the infant's display of neonatal abstinence syndrome (NAS), clinical presentation and treatment of NAS, and the impact of recent findings on future directions for research. RESULTS NAS has traditionally been described as a constellation of signs/symptoms displayed by the neonate upon withdrawal of gestational opioid exposure; however, recent research has advanced our understanding of this disorder. Other psychoactive substances, such as increasingly prescribed serotonin reuptake inhibitors, may produce an independent or synergistic discontinuation syndrome. The wide variability in NAS presentation has generated interest in the interplay of prenatal and postnatal environmental and genetic factors that may moderate or mediate its expression. Finally, recent advances in the treatment of opioid-dependent pregnant women have suggested buprenorphine as an alternative treatment to methadone during pregnancy, largely due to reduced NAS severity in exposed neonates. CONCLUSIONS Physicians should be aware of the complexity of the maternal, fetal, and infant factors that combine to create the infant's display of NAS, and incorporate these aspects into comprehensive assessment and care of the dyad. Further research regarding the pathophysiology and treatment of NAS is warranted.