In recent decades, the Fontan procedure and its variations have resulted in markedly improved outcomes of patients with single-ventricle physiology. These improvements are expected to increase greatly the number of surviving patients, particularly those surviving long into adulthood. However, there is still a progressive risk of attrition and failure of the Fontan circulation over time, the underlying pathophysiology of which is not fully understood. Current evidence suggests that alterations in the structure and function of the pulmonary vasculature may play a pivotal role. Recent evidence suggests that therapies approved for pulmonary arterial hypertension may provide benefits in this increasingly important patient population.