Cytokines and neurotrophins appear to constitute a series of self-amplifying systems in the development of essential features of ischemic neuronal injury that morphologically distinguish it in terms of either necrosis or apoptosis. An interaction of regional components at the tissue and organ level would involve vessels and particularly endothelium that are associated with proliferating glia and injured groups of neurons. It is in terms of a system of progression as applicable to cytokine action, trophic biology and gene transcription pathways that one may account for the development of ischemia as a selective susceptibility of neurons. A primary neuronal pathobiology would evolve developmentally in terms of oxidative stress, nitric oxide production and Calcium ion influx and would be reflected in lowered pH of regional tissues. Pinpointing the time of death of cells might be translated in terms of cytokine and trophic effects that promote cytoskeletal injury in the face of energy depletion. Reperfusion and no-eflow phenomena would further reflect involvement of cytokines and neurotrophins in neuronal ischemia. In fact, capillary bed loss would eventually result in central core necrosis of focal ischemic lesions that contrasts with the surrounding potentially viable penumbral zone.