The formation and accumulation of unfolded, misfolded, or damaged cellular proteins leads to development of endoplasmic reticulum stress (ER stress). A series of protective reactions is initiated in response to ER stress. These reactions are aimed at restoring the balance between protein synthesis and degradation, which is key to maintaining protein homeostasis (proteostasis). The main protective mechanisms are the attenuation of protein synthesis, increase of chaperone levels, and activation of protein degradation systems. Insufficiency or malfunction of these mechanisms induce apoptosis. Proteostasis dysregulation accompanied by protein aggregation and subsequent cell death in specific regions of the nervous system is a common pathogenetic hallmark of most neurodegenerative diseases. We discuss targeted regulation of the ER stress signaling pathways as a potential therapeutic strategy that can slow or even halt the disease progression.