Vasoplegia syndrome is a specific form of vasodilatory shock encountered in patients who undergo cardiac surgery, most commonly with cardiopulmonary bypass, which is characterized by severe hypotension in the presence of normal or increased cardiac output with abnormal tissue perfusion. Although numerous risk factors have been identified, the pathophysiology remains incompletely understood, and the therapeutic strategies are limited with a consequent poor prognosis. Current research on mechanisms and treatment has focused on targeting disequilibrium in the biological mediators of vasodilation and vasoconstriction that leads to profound hypotension and end-organ malperfusion. The morbidity and mortality rates are high, making vasoplegia syndrome a clinical area of unmet need. Looking ahead, use of standardized definitions and reporting of prospective outcomes as well as investigations into new mechanisms will be critical to identifying novel therapeutic targets and reducing the burden of vasoplegia syndrome.