In spite of much progress in understanding the mechanisms of lipoprotein metabolism at the cellular level, much less is known quantitatively about what actually occurs in vivo. A new tool for understanding the catabolic fates of lipoproteins in vivo is the use of noncatabolizable ligands for labeling proteins. These ligands are incorporated into cells with the labeled protein. The protein is catabolized but the ligand remains intact and trapped at the sites of hydrolysis as a cumulative marker of the extent of protein uptake. This tool was first applied to LDL in pigs, rats, and rabbits. In all three, hepatic catabolism predominated. Adrenal gland was the most active per unit wet weight. The trapped label methodology was also applied to the apoA-I component of HDL in rats. [3H]Cholesteryl ethers were also incorporated as noncatabolized, intracellularly trapped tracers of cholesteryl esters. Liver was the predominant site of HDL cholesteryl ether uptake, consistent with a role of HDL in reverse cholesterol transport; adrenal was the most active per unit wet weight. In adrenal, ovary, and liver, the cholesteryl ether tracer was taken up at a much greater rate than apoA-I, suggesting a mechanism for cholesteryl ester uptake independent of holo-particle uptake. Such a mechanism was verified in primary cultures of rat adrenal cells and hepatocytes.