Utilizing multiple in vitro and in vivo animal models of photoreceptor, retinal pigment epithelium (RPE), and retinal ganglion cell (RGC) injury and degeneration, we have shown that both caspase-mediated apoptosis and receptor interacting protein (RIP) kinase-mediated necrosis occurs to cause neural cell death. We have also confirmed expression of RIP kinases in human retinal specimens from eyes with macular degeneration. When caspases are effectively inhibited in these animal models, there is a shift from apoptosis to RIP-mediated necrosis and no decrease in neural cell loss overall, demonstrated by electron microscopy or biochemical methods. Thus, simultaneous inhibition of RIP kinases and caspases by exogenous delivery of inhibitors, or genetic deletion techniques, is essential for effective neuroprotection. In a model of retinal degeneration similar to retinitis pigmentosa, where rod photoreceptors harboring mutations die, followed by death of apparently normal cone photoreceptors, we have demonstrated that the two cell death pathways of apoptosis and regulated necrosis are synchronously modulated. The identification of these cell death pathways in multiple animal models, and their effective inhibition, provides the basis for novel combinatorial therapies for multiple retinal disorders, including age-related macular degeneration, retinal detachment, retinal degeneration, and glaucoma.