Endoplasmic reticulum (ER) stress is a regulatory mechanism that allows cells to adapt to a series of metabolic, redox, and other environmental changes. The role of ER stress was first identified in the maintenance of proteostasis. It has since been shown that ER stress is also critical to the regulation of lipid homeostasis, membrane turnover, and autophagy. ER stress initiates an intrinsic signaling network, the unfolded protein response, one component of the multifold and complex cellular signaling process system, which leads to major changes in the profiles of transcription factors. The unfolded protein response affects several other signaling routes through direct connections and also by indirect means. It directly influences hormone formation and life/death decisions at a cellular level; this relationship also involves connections to nutrient and environmental sensing-biotransformation processes. In conclusion, ER stress represents an integrated complex organelle response that makes an essential contribution to the maintenance of intracellular homeostasis.