There is general consensus that amphipathic α-helices and β sheets represent the major lipid-associating motifs of apolipoprotein (apo)B-100. In this review, we examine the existing experimental and computational evidence for the pentapartite domain structure of apoB. In the pentapartite nomenclature presented in this review (NH2- βα1-β1-α2- β2-α3-COOH), the original α1 globular domain (Segrest, J. P. et al. 1994. Arterioscler. Thromb. 14: 1674-1685) is expanded to include residues 1-1,000 and renamed the βα1 domain. This change reflects the likelihood that the βα1 domain, like lamprey lipovitellin, is a globular composite of α-helical and β-sheet secondary structures that participates in lipid accumulation in the co-translationally assembled prenascent triglyceride-rich lipoprotein particles. Evidence is presented that the hydrophobic faces of the amphipathic β sheets of the β1 and β2 domains of apoB-100 are in direct contact with the neutral lipid core of apoB-containing lipoproteins and play a role in core lipid organization. Evidence is also presented that these β sheets largely determine LDL particle diameter. Analysis of published data shows that with a reduction in particle size, there is an increase in the number of amphipathic helices of the α2 and α3 domains associated with the surface lipids of the LDL particle; these increases modulate the surface pressure decreases caused by a reduction in radius of curvature. The properties of the LDL receptor-binding region within the overall domain structure of apoB-100 are also discussed. Finally, recent three-dimensional models of LDL obtained by cryoelectron microscopy and X-ray crystallography are discussed. These models show three common features: A semidiscoidal shape, a surface knob with the dimensions of the βC globular domain of lipovitellin, and planar multilayers in the lipid core that are approximately 35 Å apart; the multilayers are thought to represent cholesteryl ester in the smectic phase. These models present a conundrum: Are LDL particles circulating at 37°C spheroidal in shape, as generally assumed, or are they semidiscoidal in shape, as suggested by the models? The limited evidence available supports a spheroidal shape.