Prion-related disorders (PrDs) are caused by the accumulation of a misfolded and protease-resistant form of the cellular prion, leading to neuronal dysfunction and massive neuronal loss. In human, PrDs have distinct etiologies including sporadic, infectious and familial forms, which present common clinical features; however, the possible existence of common neuropathogenic events are not known. Several studies suggest that alterations in protein folding and quality control mechanisms at the endoplasmic reticulum (ER) are a common factor involved in PrDs. However, the mechanism underlying ER dysfunction in PrDs remains unknown. We have recently reported that alterations in ER calcium homeostasis are common pathological events observed in both infectious and familial PrD models. Perturbation in calcium homeostasis directly correlated with the occurrence of ER stress and higher susceptibility to protein folding stress. We envision a model where alterations in ER function are central and common events underlying prion pathogenesis, leading to general alterations on protein homeostasis networks. © 2011 Landes Bioscience.