The recent literature has revolutionized our view on the vital importance of endoplasmic reticulum (ER)-associated degradation (ERAD) in health and disease. Suppressor/enhancer of Lin-12-like (Sel1L)–HMG-coA reductase degradation protein 1 (Hrd1)-mediated ERAD has emerged as a crucial determinant of normal physiology and as a sentinel against disease pathogenesis in the body, in a largely substrate- and cell type-specific manner. In this Review, we highlight three features of ERAD, constitutive versus inducible ERAD, quality versus quantity control of ERAD and ERAD-mediated regulation of nuclear gene transcription, through which ERAD exerts a profound impact on a number of physiological processes.