The endoplasmic reticulum (ER) lumen, which actively monitors the synthesis, folding, and modification of newly synthesized transmembrane and secretory proteins as well as lipids, is quite sensitive to homeostatic perturbations. The biochemical, molecular, and physiological events that elevate cellular ER stress levels and disrupt Ca2+ homeostasis trigger secondary reactions. These reactions are factors in the ongoing neurological pathology contributing to the continual tissue loss. However, the cells are not without defensive systems. One of the reactive mechanisms, the unfolded protein response (UPR), when evoked, provides some measure of protection, unless the stress conditions become prolonged or overwhelming. UPR activation occurs when key ER membrane-bound sensor proteins detect the excess accumulation of misfolded or unfolded proteins within the ER lumen. The activation of these sensors leads to a general protein translation shut-down, transcriptional induction, and translation of select proteins to deal with the difficult and miscreant protein or to encourage their degradation so they will do no harm. If the stress is prolonged, caspase-12, along with other apoptotic proteins, are activated, triggering programmed cell death. UPR, once considered to be a rather simple response, can now be characterized as a multifaceted labyrinth of reactions that continues expanding as research intensifies. This review will examine what has been learned to date about how this highly efficient and specific signaling pathway copes with ER stress, by centering on the basic components, their roles, and the complex interactions engendered. Finally, the UPR impact in various central nervous system injuries is summarized.