Maturation of membrane proteins is complicated by the need to fold in three distinct environments. While much is known about folding in the two aqueous milieus constituted by cytoplasm and ER lumen, our knowledge of the folding, arrangement, and quality control of transmembrane regions within the lipid bilayer, and its facilitation by molecular chaperones, is limited. New work by Bloemeke etal now reveals an expanded role of the ER chaperone calnexin acting within the lipid bilayer in a carbohydrate-independent manner.