We hypothesize that neurons have protective mechanisms against adverse local conditions that improve the chances of cell survival. In the present study, we find that growth arrest and DNA damage protein 45b (Gadd45b), a previously unknown molecule in neurons of any type, is neuroprotective in retinal ganglion cells (RGCs) in the retina. Gadd45b is upregulated in RGCs in response to oxidative stress, aging and elevated intraocular pressure. Using Gadd45b siRNA, we show that Gadd45b protects RGCs from dying against different neuronal injuries including oxidative stress, TNFalpha cytotoxicity, and glutamate excitotoxicity in vitro. Using Gadd45b knockout mice, we find that Gadd45b protects RGCs from dying against oxidative stress in vivo. Our data suggest that Gadd45b is an important component of the intrinsic neuroprotective mechanisms of RGC neurons in the retina and, perhaps in the CNS as well.