Several neurotrophic factors (NTFs) are effective in protecting retinal photoreceptor cells from the damaging effects of constant light and slowing the rate of inherited photoreceptor degenerations. It is currently unclear whether, if continuously available, all NTFs can be protective for many or most retinal degenerations (RDs). We used transgenic mice that continuously overexpress the neurotrophin NT-3 from lens fibers under the control of the αA-crystallin promoter to test for neuroprotection in light-damage experiments and in four naturally occurring or transgenically induced RDs in mice. Lens-specific expression of NT-3 mRNA was demonstrated both by in situ hybridization in embryos and by reverse-transcriptase polymerase chain reaction (RT-PCR) in adult mice. Furthermore, NT-3 protein was found in abundance in the lens, ocular fluids, and retina by enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry. Overexpression of NT-3 had no adverse effects on the structure or function of the retina for up to at least 14 months of age. Mice expressing the NT-3 transgene were protected from the damaging effects of constant light to a much greater degree than those receiving bolus injections of NT-3. When the NT-3 transgene was transferred into rd/rd, Rds/+, Q344ter mutant rhodopsin or Mertk knockout mice, overexpression of NT-3 had no protective effect on the RDs in these mice. Thus, specificity of the neuroprotective effect of NT-3 is clearly demonstrated, and different molecular mechanisms are inferred to mediate the protective effect in light-induced and inherited RDs. J. Comp. Neurol. 511:724–735, 2008. © 2008 Wiley-Liss, Inc.