Ubiquitylation is a protein modification mechanism, which is found in a multitude of cellular processes like DNA repair and replication, cell signaling, intracellular trafficking and also, very prominently, in selective protein degradation. One specific protein degradation event in the cell concerns the elimination of misfolded proteins to prevent disastrous malfunctioning of cellular pathways. The most complex of these ubiquitylation dependent elimination pathways of misfolded proteins is associated with the endoplasmic reticulum (ER). Proteins, which enter the endoplasmic reticulum for secretion, are folded in this organelle and transported to their site of action. A rigid protein quality control check retains proteins in the endoplasmic reticulum, which fail to fold properly and sends them back to the cytosol for elimination by the proteasome. This requires crossing of the misfolded protein of the endoplasmic reticulum membrane and polyubiquitylation in the cytosol by the ubiquitin-activating, ubiquitin-conjugating and ubiquitin-ligating enzyme machinery.Ubiquitylation is required for different steps of the ER-associated degradation process (ERAD). It facilitates efficient extraction of the ubiquitylated misfolded proteins from and out of the ER membrane by the Cdc48-Ufd1-Npl4 complex and thereby triggers their retro translocation to the cytosol. In addition, the modification with ubiquitin chains guarantees guidance, recognition and binding of the misfolded proteins to the proteasome in the cytosol for efficient degradation.