Neonates are in a very vulnerable state, as they adjust to their new environment and experience a period of significant physiological and psychological developmental changes. Therefore, it is important to keep in mind the role this vulnerability plays in the pharmacokinetics of administered medications due to the immaturity of the neonate'™s developing brain and hepatic function. Properly sedating this population, without over sedating them, can become problematic. The commonly used drug, midazolam, in higher doses, can lead to hypotension and decreased cerebral blood flow to an already underdeveloped cerebral vascular supply, resulting in decreased oxygenation of the brain and potential neurologic injury, principally in the form of periventricular leukomalacia (PVL). There is evidence that the alpha-2 agonist dexmedetomidine could be a safer sedation option, but it is not currently approved by the FDA for neonate use. This systematic review examines the current literature to determine if dexmedetomidine showed superiority to midazolam as a primary mechanism for neonatal sedation while appearing to provide a safer profile. This systematic review used PRISMA as a framework guideline. A literature review was conducted and data was collected in table form. A cross-study analysis was created to compare the results of these studies, which showed that midazolam in fact alters hemodynamics in neonates and had the potential to cause neurologic injury. The results urge further research to gain FDA approval of dexmedetomidine in the neonatal population and to form established guidelines for anesthesia provider reference.