The endoplasmic reticulum (ER) is a multifunctional organelle, which is crucial for correct folding and assembly of secretory and transmembrane proteins. Perturbations of ER function can cause ER stress. ER stress can activate the unfolded protein response (UPR) to cope with the accumulation of misfolded proteins and protein toxicity. UPR is a coordination system that regulates transcription and translation, leading to the recovery of ER homeostasis or cell death. However, cells have an integrated signaling system to copewith ER stress, which helps cells to restore and balance their ER function. The main components of this system are ER-associated degradation (ERAD), autophagy, hypoxia signaling, and mitochondrial biogenesis. If the balance cannot be restored, the imbalance will lead to cell death or apoptosis, or even to a series of diseases. In this review, a series of activities to restore the homeostasis of cells during ER stress are discussed.