Serotonin (5-HT) and voltage-gated potassium (KV) channels have emerged as two major factors in the pathogenesis of pulmonary arterial hypertension (PAH). In pulmonary artery smooth muscle cells (PASMC), KV channels play a major role in the regulation of pulmonary arterial tone and proliferation. Thus, activation of KV channels leads to vasodilatation and enhances apoptosis, while their inhibition is associated with vasoconstriction and proliferation in PASMC. Moreover, these channels have a prominent role as a common target for pulmonary vasoconstrictors. Modulation of these channels by vasoconstrictors involves the activation of a variety of protein kinases. Here we review the role of localization and internalization as a novel mechanism for acute regulation of KV channels and pulmonary vascular tone by agonists such as serotonin.