Apolipoprotein (apo)C-I and apoC-III are constituents of HDL and of triglyceride-rich lipoproteins that slow the clearance of triglyceride-rich lipoproteins by a variety of mechanisms. ApoC-I is an inhibitor of lipoprotein binding to the LDL receptor, LDL receptor-related protein, and VLDL receptor. It also is the major plasma inhibitor of cholesteryl ester transfer protein, and appears to interfere directly with fatty acid uptake. ApoC-III also interferes with lipoprotein particle clearance, but its principal role is as an inhibitor of lipolysis, both through the biochemical inhibition of lipoprotein lipase and by interfering with lipoprotein binding to the cell-surface glycosaminoglycan matrix where lipolytic enzymes and lipoprotein receptors reside. Variation in the expression of apoC-III has been credibly documented to have an important role in hypertriglyceridemia. Variation in the expression of apoC-I may also be important for hypertriglyceridemia under certain circumstances.