The endoplasmic reticulum (ER) is the site for maturation of proteins destined for the secretory pathway. Failure in maturation leads to production of misfolded proteins that are eliminated through the ER-associated degradation (ERAD) pathway. ERAD is a complex process that includes misfolded protein recognition, retrotranslocation to the cytosol, ubiquitination and proteasomal degradation. gp78 is an E3 ubiquitin ligase that integrates these ERAD steps by nucleating a unique degradation machine, which uses the p97/VCP-Npl4 complex for retrotranslocation instead of the wellknown p97/VCP-Ufd1-Npl4 complex. A growing list of substrates have been identified for gp78, which highlights the importance of gp78-mediated ERAD in essential physiological pathways and pathological processes.