Protein homeostasis (proteostasis) is essential for cellular health, ensuring proper protein conformation, concentration, and localization. This chapter focuses on two critical cellular systems that maintain proteostasis: the endoplasmic reticulum (ER) with protein quality control and the ubiquitin-proteasome system (UPS). The ER, site of synthesis for secretory and membrane proteins, faces the challenge of correctly folding a large portion (~30%) of the proteome. A significant fraction of newly synthesized proteins misfolds, necessitating robust quality control mechanisms. The ER employs chaperones and folding enzymes to assist in proper folding, and disposes of terminally misfolded proteins via ER-associated degradation and ER-phagy, a specialized form of autophagy. These processes are tightly regulated by the unfolded protein response, a complex signaling system activated by ER stress. On the other hand, UPS, a major degradation pathway, targets proteins for destruction via ubiquitylation. It plays a crucial role in removing damaged or misfolded proteins, regulating protein levels, and maintaining cellular and organellar homeostasis. This chapter explores the intricate interplay between the ER and UPS in maintaining proteostasis, highlighting their individual functions, cooperative roles, and implications in cellular health and disease.