Topical (eye-drop) application of a highly specific caspase-9 inhibitor reduces retinal ischemia and provides robust morphologic, cellular, and functional neuroprotection; genetic deletion of caspase-9 from endothelial cells phenocopies the protective effects of pharmacological caspase-9 inhibition, identifying specifically endothelial caspase-9 activity as the proximal event in hypoxia/ischemia-induced neuronal injury. Here, CASP9 is linked to retinal ischemia.