Mechanical ventilation is a stressful experience in neonates resulting in changes in neuroendocrine parameters, pain scores, and physiologic responses. Assisted ventilation in neonates is presumed to be associated with chronic repetitive pain, which in turn is associated with adverse long-term sequelae. Reasons to routinely sedate ventilated neonates include improved ventilator synchrony, improved pulmonary function, and decreased neuroendocrine responses, including cortisol, beta-endorphine, and catecholamines. Reasons not to treat include the well-known adverse side effects of pain medication, especially the opiates, including hypotension from morphine, chest wall rigidity from fentanyl, and tolerance, dependence, and withdrawal from both opiates and benzodiazepines. Additionally, adverse effects such as death and IVH are not improved with preemptive treatment. Chronic pain assessment is poorly validated and difficult to assess in this population, and most studies have evaluated only acute pain scores. If patients are treated, opiates are the most common class of drugs, with morphine the most well studied. Fentanyl may be advantageous in hypotensive, younger neonates because it has fewer cardiovascular effects. The benzodiazepines, midazolam and lorazepam, have been used in ventilated neonates, but midazolam has been associated with adverse effects in one small study so concern remains regarding its use. Significant gaps in our knowledge exist, especially in regard to long-term effects of treatment, or lack thereof, and in the assessment of the chronic pain associated with assisted ventilation.