Pulmonary arterial hypertension (PAH) is progressive disorder characterized by elevated pulmonary vascular resistance that can lead to right heart failure and death. One of the main therapeutic options for PAH are medications targeting the prostacyclin pathway. Treprostinil is a prostacyclin analogue and selexipag is a selective IP receptor agonist. Treprostinil can be delivered by a variety of routes including oral, inhaled, subcutaneous and intravenous. Selexipag is currently approved as an oral formulation. The impact of the route of delivery and the optimal dosing for transitioning inhaled treprostinil to oral treprostinil or selexipag is unknown. More importantly, given the different selectivity for prostacyclin receptors, it is uncertain whether treprostinil and selexipag can be substituted. We present two patients with PAH who received medications targeting the prostacyclin pathway and were transitioned from inhaled treprostinil to either oral treprostinil or selexipag. In both cases, we noted clinical, functional and hemodynamic deterioration. These cases highlight that the route of delivery (inhaled versus oral) and/or the specific PH medication (treprostinil versus selexipag) matter; therefore close monitoring during transitions is imperative.