The application of positive-pressure mechanical ventilation is one of the cornerstones of support for patients with acute respiratory failure. Unfortunately, the clinical condition of some patients does not improve, despite escalating ventilatory support. Adjunctive therapies to mechanical ventilation such as nitric oxide and heliox have been explored for the purposes of minimizing injurious settings and supporting adequate gas exchange. As specific therapies continue to evolve, clinicians should have a clear understanding of the physiologic basis and evidence before deciding to use any adjunctive therapy. This article discusses the role of nitric oxide and heliox as adjunct therapies to mechanical ventilation. Many questions remain about the role of these unique gases in the management of pediatric patients with acute respiratory failure. Should nitric oxide be used outside of its approved indication, and should heliox be used at all due to the lack of definitive evidence?