Calcitonin gene-related peptide (CGRP)-targeted therapies are a recent addition to the migraine field. Monoclonal antibodies became available in 2018 and gepants in 2020, both now widely used for migraine prevention and acute treatment. CGRP is also a potent endogenous pulmonary vasodilator, and its blockade worsens pulmonary hypertension in experimental models. Yet the cardiopulmonary risks of CGRP pathway inhibition in humans have not been studied systematically. We report 3 patients with hemodynamically confirmed pulmonary arterial hypertension (PAH) diagnosed while they were receiving CGRP-targeted therapy. Two patients lacked traditional PAH risk factors; the third patient had suspected portal hypertension. All patients presented with markedly elevated pulmonary vascular resistance, and 2 patients improved after CGRP-targeted therapy was discontinued and PAH treatment was initiated. Although causality cannot be inferred from these cases, the temporal association and biologic plausibility suggest a potential safety signal deserving of further study. Clinicians should remain vigilant for cardiopulmonary symptoms in patients receiving CGRP-targeted therapies.