Platypnea-orthodeoxia is a poorly understood clinical syndrome resulting in dyspnea and hypoxemia in the upright position, which diminishes with recumbency. Recognition of the disease is limited by its low prevalence and decreased awareness among clinicians. However, understanding the disease, its pathophysiology, its clinical presentation, and the possible therapeutic options is vital in the management of these patients. Here, we present 2 cases of platypnea- orthodeoxia where oxygen saturations worsened with hemodialysis. After highlighting the common features in the clinical pattern of each patient, we present a pressure-mediated pathophysiologic mechanism (in contrast to a previously reported morphologically based hypothesis) to explain the characteristic effects of hemodialysis on hypoxia in platypnea-orthodeoxia. We present a novel diagnostic approach using balloon occlusion testing when the diagnosis is unclear and illustrate how treatments can be tailored to the comorbidities of a specific patient.