Protein folding in the endoplasmic reticulum (ER) is monitored by ER quality control (ERQC) mechanisms. Proteins that fail ERQC criteria are degraded through the ER-associated degradation (ERAD) pathway, where molecular chaperones and associated factors recognize and target substrates for retrotranslocation to the cytoplasm, where they are degraded by the ubiquitin-proteasome machinery. The discovery of diseases associated with ERAD has highlighted its importance. This review summarizes the current understanding of each step in ERAD, including substrate recognition, targeting, retrotranslocation, ubiquitylation, and proteasomal degradation. It discusses how ERAD efficiency is regulated and the intersection between ERAD, autophagy, and the unfolded protein response (UPR), which can lead to apoptosis if unmitigated. The relationship between ER-protein folding, ERAD, and protein transport to later compartments of the secretory pathway is also surveyed.Protein folding in the endoplasmic reticulum (ER) is monitored by ER quality control (ERQC) mechanisms. Proteins that fail ERQC criteria are degraded through the ER-associated degradation (ERAD) pathway, where molecular chaperones and associated factors recognize and target substrates for retrotranslocation to the cytoplasm, where they are degraded by the ubiquitin-proteasome machinery. The discovery of diseases associated with ERAD has highlighted its importance. This review summarizes the current understanding of each step in ERAD, including substrate recognition, targeting, retrotranslocation, ubiquitylation, and proteasomal degradation. It discusses how ERAD efficiency is regulated and the intersection between ERAD, autophagy, and the unfolded protein response (UPR), which can lead to apoptosis if unmitigated. The relationship between ER-protein folding, ERAD, and protein transport to later compartments of the secretory pathway is also surveyed.