Few controlled trials exist to demonstrate the efficacy and the risks of pharmacologic agents used in treating pediatric, and more specifically neonatal patients. It is not different for the central nervous system altering class of drugs, benzodiazepines (BZDs). Little information is known about the long-term effects of BZDs use in neonates as anxiolytics and sedatives causing trepidation with their use in the clinical setting. Insufficient data related to the use of BZDs result in a lack of clear recommendations to guide caregivers at the bedside on the safest administration patterns to avoid long-term adverse effects. However, caring for ill neonates, in particular surgical patients and infants requiring prolonged hospitalizations, necessitates the use of these agents. A literature search within the electronic database, PubMed, of English language, full-text articles published between 2007 and 2012 was undertaken to determine the state of the science regarding the use of BZDs in neonates. These medications cause unwanted effects in neonates with immature hepatic function (primary site of metabolism) and during a developmental period of tremendous neuroplasticity. It benefits caregivers to recognize the need for improved monitoring of stress experienced by infants in the NICU and understand the impact of prolonged agitation and subacute pain on infant development.