Endoplasmic reticulum-associated degradation (ERAD) is a critical quality control mechanism responsible for eliminating misfolded or unassembled proteins. It maintains endoplasmic reticulum homeostasis, ensures a proper folding environment and regulates substrate protein levels. Following its discovery in the late 1980s and early 1990s, research on ERAD in mammals-particularly that mediated by the conserved protein complex comprising suppressor/enhancer of Lin-12-like protein 1-like (SEL1L) and HMG-CoA reductase degradation protein 1 (HRD1)-has advanced substantially over the past decade. SEL1L-HRD1-mediated ERAD is now recognized as a fundamental process in mammals that governs various physiological functions largely in a substrate-specific manner. In humans, mutations in this complex have been causally linked to ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) and ENDI-agammaglobulinaemia. This Review highlights the SEL1L-HRD1-mediated ERAD pathway, exploring its machinery, molecular mechanism and physiological relevance and potential therapeutic strategies targeting this system.