Erdheim-Chester disease (ECD) is a rare inflammatory myeloid neoplasm characterized by multi-organ non-Langerhans fibrohistiocytosis. The pleuropulmonary involvement observed in ECD is caused by infiltration of clonal histiocytes, resulting in diffuse and focal patterns of pleural thickening, fluid accumulation within the pleural space, and infiltrative parenchymal/mediastinal disease. This chapter examines our understanding of the pathophysiology, clinicoradiopathologic presentation, diagnosis, treatment, and prognosis of pleuropulmonary ECD, building on documented observations through a review of Mayo Clinic cases with biopsy-proven pleural and lung involvement.