Abstract: Synaptic activity and ischemia/injury promote lipid messenger formation through phospholipase-mediated cleavage of specific phospholipids from membrane reservoirs. Lipid messengers modulate signaling cascades, contributing to development, differentiation, function (e.g., memory), protection, regeneration, and repair of neurons and overall regulation of neuronal, glial, and endothelial cell functional integrity. Oxidative stress disrupts lipid signaling and promotes lipid peroxidation and neurodegeneration. Lipid signaling at the neurovascular unit (neurons, astrocytes, oligodendrocytes, microglia, and cells of the microvasculature) is altered in early cerebrovascular and neurodegenerative disease. We discuss how lipid signaling regulates critical events in neuronal survival. Aberrant synaptic plasticity (e.g., epileptogenesis) is highlighted to show how gene expression may drive synaptic circuitry formation in the “wrong” direction. Docosahexaenoic acid has been implicated in memory, photoreceptor cell biogenesis and function, and neuroprotection. Free docosahexaenoic acid released in the brain during experimental stroke leads to the synthesis of stereospecific messengers through oxygenation pathways. One messenger, 10,17S-docosatriene (neuroprotectin D1; NPD1), counteracts leukocyte infiltration and proinflammatory gene expression in brain ischemia-reperfusion. In retina, photoreceptor survival depends on retinal pigment epithelial (RPE) cell integrity. NPD1 is synthesized in RPE cells undergoing oxidative stress, potently counteracts oxidative stress-triggered apoptotic DNA damage in RPE, upregulates antiapoptotic proteins Bcl-2 and Bcl-xL, and decreases proapoptotic Bax and Bad expression. These findings expand our understanding of how the nervous system counteracts redox disturbances, mitochondrial dysfunction, and proinflammatory conditions. The specificity and potency of NPD1 indicate a potential target for therapeutic intervention for stroke, age-related macular degeneration, spinal cord injury, and other neuroinflammatory or neurodegenerative diseases.