Mutation of the Tub gene results in the mislocalization of photoreceptor-specific proteins and eventually retinal degeneration. However, the exact mechanism underlying the retinal degeneration remains largely unknown. In this study, we discovered that the expression of endoplasmic reticulum (ER) stress markers, IRE1, ATF6, eIF2α, GRP78/BiP, and XBP-1, is up regulated during tubby retinal development. The dynamics of the expression of these genes are time-dependent and coincided with the time-course of photoreceptor death. Our data also demonstrated that ER stress triggers apoptosis via down-regulation of Bcl2, up-regulation of CHOP and the activation of NF-кB signaling.