Protein misfolding and aggregation in the endoplasmic reticulum (ER) have been causally linked to a variety of human diseases. Two key pathways for eliminating misfolded proteins and aggregates in the ER are ER-associated degradation (ERAD) and ER-phagy, respectively. While both pathways have been well characterized biochemically, our understanding of their physiological relevance and significance remains limited. In recent years, significant advances have been made, including the generation and characterization of various knockout and knockin mouse models, the identification of human disease-associated or -causing variants, and insights into the coordination between ERAD and autophagy in physiological contexts. In this review, we summarize these advancements, highlighting the key roles of a highly conserved suppressor of lin-12-like-hydroxymethyl glutaryl-coenzyme A reductase degradation 1 (SEL1L-HRD1) protein complex of ERAD and ER-phagy in health and disease.