Because the levels of secreted apolipoprotein B (apoB) directly correlate with circulating serum cholesterol levels, there is a pressing need to define how the biosynthesis of this protein is regulated. Most commonly, the concentration of a secreted, circulating protein corresponds to transcriptionally and/or translationally regulated events. By contrast, circulating apoB levels are controlled by degradative pathways in the cell that select the protein for disposal. This article summarizes recent findings on two apoB disposal pathways, endoplasmic reticulum (ER)-associated degradation and autophagy, and describes a role for post-ER degradation in the increased circulating lipid levels in insulin-resistant diabetics.