Platypnea–orthodeoxia syndrome (POS) is a rare disorder characterized by the emergence of a right-to-left shunt at the intracardiac or intrapulmonary level. The clinical picture is distinguished by shortness of breath that worsens on standing due to an accentuation of oxygen desaturation, and instead improves, at least partly, in the recumbent position. In this article we present a brief review of the pathophysiology of POS, as well as its clinical picture, diagnostic assessment, and preferential therapeutic options. Pathophysiological issues that are still not completely understood or much debated are outlined. The currently accepted pathophysiological concepts are presented and a summary of the main diagnostic and therapeutic tools is provided.