Apoptosis of photoreceptor cells in the early postnatal period is a normal feature of mammalian retinal development. The role of mitochondria and caspases in the process has been well established; however, the identification of key apoptotic mediators still remains elusive. Here we report that BIMEL, a pro-apoptotic BCL-2 family member, may be one such molecule. Following growth factor deprivation, BIMEL was up-regulated in mouse 661W cone photoreceptors. This event correlated with the release of mitochondrial apoptogenic factors into the cytosol, the activation of caspases and apoptosis. Moreover, a similar behaviour was observed in response to UV radiation, ionomycin or H2O2 treatments. We identified the PI3K-Akt-FKHRL1 signalling cascade as the main regulatory pathway of BIMEL expression in these cells. Finally, using RNA interference, we were able to silence BIMEL expression and subsequently suppress caspase-3 activation. In conclusion, we propose BIMEL as a critical factor in mitochondria-dependent apoptosis of 661W photoreceptors.