Several metabolic molecules have harmful effect on clinical outcomes. Usually serum levels are controlled by medications. However, in certain clinical scenarios, conservative treatment fails to achieve its therapeutic goals (familial hypercholesterolemia and fulminant Wilson’s disease) and direct removal by PEX or other apheresis modalities (e.g. lipoprotein  apheresis) may be required. The chapter will review the major indications for PEX in endocrinology and metabolic disease.