As the opioid epidemic escalates in westernized countries around the world, chronic opioid use during pregnancy has become a growing public health issue. There are increasing concerns that chronic maternal opioid use might adversely affect the developing fetal brain. Furthermore, the sudden discontinuation of the trans-placental opioid supply at birth puts newborns at acute risk for neonatal opioid withdrawal syndrome (NOWS). NOWS is a multi-system disorder that has been identified in approximately 50-80% of neonates exposed to opioids due to chronic maternal use. Clinically, NOWS affects the central and autonomic nervous systems as well as the gastrointestinal and respiratory tracts. The clinical features of NOWS include hyperirritability, high-pitched crying, restlessness, tremors, poor sleep, agitation, seizures, sweating, fever, poor feeding, regurgitation, diarrhea, and tachypnea. NOWS is currently diagnosed using a clinical scoring tool followed by toxicological confirmation of the presence of opioids in meconium or tissue specimens. The first-line treatments for NOWS are non-pharmacologic comfort measures. If these measures fail, neonates may be treated with opioids and/or sedatives. Since the severity of NOWS can be highly variable, it is quite difficult to predict which opioid-exposed neonates will require pharmacotherapy and prolonged hospitalization. Factors associated with maternal polysubstance use, including the use of illicit substances and tobacco, have been associated with the increased severity and duration of NOWS. Since neonates with NOWS are at increased risk for long-term adverse neurodevelopmental outcomes, ongoing monitoring beyond the neonatal period is essential.