The myelin-associated membrane protein reticulon-4 (RTN4)/Nogo has been extensively studied with regards to its neurite outgrowth inhibitory function, both in limiting plasticity in the healthy adult brain and regeneration during central nervous system injury. These activities are presumably associated with Nogo splice isoforms expressed on the cell surface and function largely in trans, exerting an influence as an intercellular membrane-bound ligand. Nogo, and other reticulon paralogues and orthologues, are however mainly localized to the endoplasmic reticulum (ER), and are likely to have cell autonomous functions that are not yet clear. Emerging evidence suggests that Nogo may have a role in modulating the morphology and functions of the ER. This role is apparently not essential for cell viability under normal growth conditions, but may be manifested under certain stress conditions. J. Cell. Physiol. 216: 303–308, 2008. © 2008 Wiley-Liss, Inc.