Severe pediatric ARDS remains a significant challenge for clinicians, and management strategies are essentially limited to lung protective ventilation strategies, and adjunct approaches such as prone positioning, steroids, surfactant, and inhaled nitric oxide in unique situations. Inhaled nitric oxide produces pulmonary vasodilation in ventilated regions of the lung, shunting blood away from poorly ventilated areas and thus optimizing the ventilation perfusion ratio. A subset of patients with ARDS are known to be non-responders to nitric oxide, and selective pulmonary vasodilators such as Epoprostenol can be useful as rescue therapy in such cases. We describe a case of severe pediatric ARDS in the setting of pre-existing pulmonary hypertension and Trisomy 21, whose clinical course improved remarkably once inhaled Epoprostenol was initiated.