The platypnea-orthodeoxia syndrome is a rare but important condition caused by a variety of clinical entities. Several mechanisms have been postulated to cause platypnea and orthodeoxia. These mechanisms mainly involve intracardiac shunting, pulmonary vascular shunting, and ventilation-perfusion mismatching. Patent foramen ovale is an important type of intracardiac shunt that can produce platypnea-orthodeoxia in select patients. Concomitant pulmonary hypertension must be ruled out, but symptoms can occur without pulmonary hypertension in cases with altered intrathoracic anatomy and physiology. Diagnosis usually entails transthoracic or trans-esophageal echocardiogram, ideally with postural provocation by the tilt-table test. Treatment with surgical or percutaneous closure may result in symptomatic relief. The decision to intervene is based mainly on the severity of symptoms and potential morbidities associated with the defect.