Endotracheal intubation, a common procedure in neonatal intensive care, results in distress and disturbs physiologic homeostasis in the newborn. Analgesics, sedatives, vagolytics, and/or muscle relaxants have the potential to blunt these adverse effects, reduce the duration of the procedure, and minimize the number of attempts necessary to intubate the neonate. The medical care team must understand efficacy, safety, and pharmacokinetic data for individual medications to select the optimal cocktail for each clinical situation. Although many units utilize morphine for analgesia, remifentanil has a superior pharmacokinetic profile and efficacy data. Because of hypotensive effects in preterm neonates, sedation with midazolam should be restricted to near-term and term neonates. A vagolytic, generally atropine, blunts bradycardia induced by vagal stimulation. A muscle relaxant improves procedural success when utilized by experienced practitioners; succinylcholine has an optimal pharmacokinetic profile, but potentially concerning adverse effects; rocuronium may be the agent of choice based on more robust safety data despite a relatively prolonged duration of action. In the absence of an absolute contraindication, neonates should receive analgesia with consideration of sedation, a vagolytic, and a muscle relaxant before endotracheal intubation. Neonatal units must develop protocols for premedication and optimize logistics to ensure safe and timely administration of appropriate agents.