The endoplasmic reticulum (ER) is a cellular organelle found in virtually every human cell. The ER participates in many important cellular tasks, including protein and lipid biosynthesis, calcium regulation, redox regulation (regulation of oxidative stress), and cell death. Given the many vital and complex functions of the ER, it is little wonder that its failure can trigger a range of diseases. Recent genetic and clinical evidence indicates that inherited or acquired dysregulation of ER homeostasis can give rise to genetic diseases, including Wolfram syndrome characterized by juvenile-onset diabetes and neurodegeneration, as well as a number of common diseases, including diabetes, Parkinson’s disease, and Alzheimer’s disease. The primary dysfunction of ER tends to cause early-onset and inherited genetic diseases. In contrast, the secondary dysfunction of ER tends to cause diseases associated with age, such as type 2 diabetes and neurodegeneration. Wolfram syndrome is caused by the primary dysfunction of ER.