Dexamethasone treatment of neonates to facilitate weaning from mechanical ventilation has become increasingly common. Despite thousands of infants being treated, most studies fail to demonstrate an improvement in long-term pulmonary and neurodevelopmental outcome. Much controversy remains regarding who should be treated, when treatment should begin, what the proper dose is, how long treatment should continue, and how adverse effects can be minimized. Early treatment prior to the onset of significant pulmonary inflammation may be an approach that improves outcomes and allows for shorter treatment courses. Risk assessment tools using ventilator requirements, adrenal function, or markers of pulmonary inflammation may allow for improved patient selection. Future studies will need to include a large number of subjects and will need to be continued beyond the neonatal period to assess long-term pulmonary and neurodevelopmental outcome.