Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are critical cellular processes that play a significant role in the development of various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis. These disorders are characterized by the accumulation of misfolded proteins, leading to cellular dysfunction and cell death. The ER is essential for the proper folding of proteins, and disruptions in its function can cause an accumulation of unfolded or misfolded proteins, resulting in ER stress. The UPR is an adaptive response aimed at restoring ER homeostasis, but chronic activation of the UPR can contribute to disease progression. This chapter delves into the molecular mechanisms underlying ER stress and the UPR, exploring their roles in neurodegenerative diseases and highlighting the complex signaling pathways involved, including the roles of key regulators such as PERK, IRE1, and ATF6, and examines how ER stress interacts with other cellular processes, such as mitochondrial dysfunction and oxidative stress, further aggravating neurodegeneration. Recent discoveries in the molecular mechanisms of ER stress and UPR offer promising therapeutic targets. By modulating these pathways, it may be possible to develop strategies to alleviate ER stress, enhance protein folding capacity, and improve cellular resilience. This chapter offers an extensive summary of the existing knowledge, laying the groundwork for future research efforts and the development of new therapeutic approaches in treating neurodegenerative diseases.