Endoplasmic reticulum (ER), principal but complex, functions as the pleiotropic organelle for proper protein folding, Ca²⁺ storage as well as lipid and carbohydrate metabolisms. Diverse microenviromental insults including, but not limited to, inflammatory reaction, glucose imbalance and hypoxia, elicit the accumulation of potentially toxic unfolded proteins in the ER lumen. Under the condition of these cellular threats, the autophagy with the well-orchestrated program containing over 30 autophagy-related genes (ATGs) might be initiated for degrading and recycling of the cumulative misfolded proteins and other related abnormal cytoplasmic components. The link between UPR and autophagy has been verified as the PERK-eIF2α-ATF4 signaling pathway by ongoing research, and the transcription factor C/EBP homologous (CHOP) mediated by ATF4 were further substantiated to regulate a dozen of ATG genes transcriptionally. Recent researches showed that the crosstalk between these signaling systems might mainly account for chemotherapy resistance in many cancers because the chemoresistant phenotypes are usually concomitant with increasing autophagy when drugs were administrated to trigger inflammatory microenvironment and other dyshomeostasis. We summarized recent researches in the molecular link between UPR and autophagy signaling pathways as well as the perspectives of potential inhibitors targeting the Achilles heel for further clinical use.