Given the putative role of pulmonary vasoconstriction in PAH, vasodilators were a natural initial therapeutic choice. Over the past 40 years, a large number of agents from different classes, including adrenergic agonists (eg, isoproterenol) and antagonists (eg, phentolamine), arterial vasodilators (eg, hydralazine), nitrates (eg, nitroglycerin), angiotensin-converting enzyme inhibitors, calcium-channel blockers (CCBs), and prostaglandins have been administered to patients with PAH. Many were initially hailed as “effective,” “life-saving” “breakthroughs” based on the strength of case reports and uncontrolled case series. However, most have been consigned to the dustbin of failed PAH therapies because of lack of long-term symptomatic, functional, or survival benefit. In addition, long-term administration of several of these vasodilators has been associated with significant adverse effects, including worsening RV function and increased mortality.