Lipoprotein metabolism is the result of a complex network of many individual components. Abnormal lipoprotein concentrations can result from changes in the production, conversion, or catabolism of lipoprotein particles. Studies in hypolipoproteinemia and hyperlipoproteinemia have elucidated the processes that control VLDL secretion as well as VLDL and LDL catabolism. Here, we review the current knowledge regarding apolipoprotein B (apoB) metabolism, focusing on selected clinically relevant conditions. In hypobetalipoproteinemia attributable to truncations in apoB, the rate of secretion is closely linked to the length of apoB. On the other hand, in patients with the metabolic syndrome, it appears that substrate, in the form of free fatty acids, coupled to the state of insulin resistance can induce hypersecretion of VLDL-apoB. Studies in patients with familial hypercholesterolemia, familial defective apoB, and mutant forms of proprotein convertase subtilisin/kexin type 9 show that mutations in the LDL receptor, the ligand for the receptor, or an intracellular chaperone for the receptor are the most important determinants in regulating LDL catabolism. This review also demonstrates the variance of results within similar, or even the same, phenotypic conditions. This underscores the sensitivity of metabolic studies to methodological aspects and thus the importance of the inclusion of adequate controls in studies.