The endoplasmic reticulum (ER) is a subcellular compartment playing a central role in calcium storage and signaling. Disturbances of ER calcium homeostasis constitute a severe form of stress interfering with central functions of this structure including the folding and processing of newly synthesized membrane and secretory proteins. Blocking the folding and processing reactions results in the accumulation of unfolded proteins forming potentially toxic aggregates. To restore ER functioning, specific stress responses are activated one of which is the unfolded protein response (UPR). UPR is characterized by a shutdown of global protein synthesis and activation of expression of genes coding for ER-resident proteins that are involved in the folding and processing reactions. ER calcium homeostasis is therefore inevitably associated with major cellular functions, including gene transcription and translation. ER calcium homeostasis und ER functions are believed to be impaired in various degenerative diseases of the brain including Alzheimer's, Parkinson's and Huntington's disease, and amyotrophic lateral sclerosis. ER functioning has also been shown to be disturbed in acute pathological states of the brain such as ischemia and trauma, which have been identified as risk factors for the development of degenerative diseases. This implies that there are common underlying pathomechanisms. This review will summarize new observations suggesting that impairment of ER functioning may be a common denominator of pathological processes resulting in neuronal cell injury in acute disorders and degenerative diseases of the brain.