Cardiovascular disease is a major cause of human morbidity and mortality. Drug strategies for the prevention of the disease are largely centered on the interaction of low‐density lipoprotein receptor (LDLR) with the apolipoprotein B‐100 (apoB‐100) protein on low‐density lipoprotein (LDL). Recently, the structure of apoB‐100 on LDL was determined in the absence and presence of LDLR, using cryo‐electron microscopy. A remarkable structural feature of apoB‐100 is the lack of any significant tertiary structure within the C‐terminal two‐thirds of the protein (>3000 residues). Instead, apoB‐100 forms amphipathic helices and β‐sheets on the phospholipid surface of LDL, which envelops its neutral lipid core. The apoB‐100 ligand binding domain for LDLR includes multiple points on a circumferential β‐belt and on the N terminus. In the course of this study, we also observed several instances of structural heterogeneity in apoB‐100. The various conformations may allow apoB‐100 to accommodate different size lipoprotein particles and to permit recognition by other apolipoproteins or receptors.