Acid sensing ion channel 1 (ASIC1) belongs to the amiloride-sensitive, degenerin/epithelial sodium channel (DEG/ENaC) superfamily. ASIC1 is a voltage-independent, proton-gated cation channel and its activity has been linked to a variety of physiological and pathological functions in the central and peripheral nervous system. The influx of Na+ and Ca2+ through these channels contributes to membrane potential regulation, activation of Ca2+/calmodulin-dependent mechanisms, and other second-messenger pathways signifying the diverse role ASIC1 plays in intracellular signaling and excitability. ASIC1 is also expressed in variety of vascular cells and our research program has focused on the novel role for ASIC1 in regulating pulmonary arterial smooth muscle cell (PASMC) Ca2+ influx in both physiological and pathophysiological settings. Through a store-operated mechanism, ASIC1 contributes to pulmonary vasoconstriction elicited by various agonists and alveolar hypoxia. Enhanced ASIC1-mediated Ca2+ entry in PASMC is a central component to the active vasoconstriction, vascular remodeling, and right ventricular hypertrophy associated with the development of hypoxic pulmonary hypertension. Despite the requirement for ASIC1 to enhanced Ca2+ influx in the pulmonary hypertensive circulation, these responses are not dependent on an increase in PASMC ASIC1 protein expression. Rather, hypoxia promotes activation of ASIC1 through a RhoA-dependent increase in ASIC1 plasma membrane localization. ASIC1 is also redox-sensitive, and we have characterized some unique relations between hypoxia-induced changes in reactive oxygen species homeostasis with that of ASIC1 function. Ultimately, a better understanding of the molecular mechanisms by which ASIC1 is regulated will help elucidate their role in the development of pulmonary hypertension.