Apolipoprotein B100 (apoB) is a large amphipathic lipid-binding protein that is synthesized by hepatocytes and used to assemble and stabilize very low density lipoproteins (VLDL). It may have been derived through evolution from other lipid-associating proteins such as microsomal triglyceride transfer protein or vitellogenin. The correct folding of apoB requires assistance from chaperone proteins in co-translational lipidation, disulfide bond formation, and glycosylation. Any impairment in these processes results in co-translational targeting of the misfolded apoB molecule for proteasomal degradation. In fact, most of the regulation of apoB production is mediated by intracellular degradation. ApoB that misfolds post-translationally, perhaps as a result of oxidative stress, may be eliminated through autophagy. This review focuses on the proposed pentapartite domain structure of apoB, the role that each domain plays in the binding of lipid species and regulation of apoB synthesis, and the process of VLDL assembly. The factors involved in the recognition, ubiquitination, and proteasomal delivery of defective apoB molecules are also discussed.