Multiple pregnancy newborns, particularly twins, will generally experience favorable short term outcomes and develop normally. However, these infants will occasionally present significant challenges to the neonatal care provider due to difficulties in extrauterine life adaptation, a spectrum of organ immaturity conditions resulting from preterm delivery, and other biologic risks. Adverse outcomes more likely to present in multiples include intrauterine growth restriction, placental complications, prematurity-related conditions, and congenital anomalies. These infants, even when born extremely premature, are more likely to survive today than years ago due to vast improvements in high risk obstetric and neonatal intensive care. Given the increased likelihood of high-risk conditions and complications, multiple pregnancy newborns should be delivered in hospitals with trained, experienced staff to support the newborns’ immediate needs and better ensure their optimal outcomes. Families of multiples may be at greater risk for stress, anxiety, and depression, and may require specialized and individualized teaching, counseling, and support during the newborns’ admission and after discharge.