Soluble guanylyl cyclase (sGC) catalyzes cyclic guanosine 3’,5’–monophosphate (cGMP) synthesis. cGMP is involved in relaxation of vascular smooth muscle, modulation of inflammation, inhibition of platelet aggregation, and control of vascular permeability. sGC is the intracellular receptor for nitric oxide (NO) or a nitroso intermediate and has been reported to be the active moiety in traditional organic nitrate therapy used in congestive heart failure and angina pectoris. Low dose organic nitrate therapy has been experimentally used to improve blood flow in shock states from sepsis. Inhaled NO is used in persistent pulmonary hypertension of the newborn and in the intensive care unit for right heart protection following cardiac transplantation. However, NO requires a functional heme-moiety on sGC for activation. The effectiveness of NO is reduced when the heme-moiety is oxidized causing endothelial dysfunction. In this review we discuss animal studies and early clinical trials with agents that stimulate sGC and discuss potential clinical applications in pulmonary hypertension and in perioperative care.