Three illustrative cases of refractory hypoxemia in adults are presented. In two cases contrast echocardiography was invaluable in establishing the diagnosis of a true anatomic right to left shunt, as well as in localizing the shunt to an intracardiac or extracardiac site. In the third case true anatomic right to left shunt was excluded by means of contrast echocardiography. The pathophysiology of hypoxemia is discussed with emphasis on the potential diagnostic utility of contrast echocardiology in patients with refractory hypoxemia. A diagnostic flow chart is proposed.