Urban planning of the endoplasmic reticulum (ER): How diverse mechanisms segregate the many functions of the ER

► This review summarizes mechanisms that lead to the targeting of ER proteins to individual membrane domains (e.g., rough ER). ► Formation of interactions between the Sec61 proteins, ribosomes and mRNAs is critical for rough ER targeting. ► The equilibrium between atlastins, reticulons and DP1/Yop1p determines the formation of smooth ER tubules. ► Targeting to the MAM depends on ER redox and on cytosolic or mitochondrial sorting motifs. ► Targeting to ERES, ERQC, and sites of peroxisome and lipid droplet biogenesis depend on COPI and COPII proteins.