Although it was initially Antoine Lavoisier who determined that oxygen is the only gas in air that sustains pulmonary respiration to prevent death and that almost 200 years later Barcroft introduced the terms "anoxic", "anemic", "histotoxic", and "stagnant" to designate the various forms of anoxia, our comprehension of human anoxic brain injury is far from complete. The term cerebral anoxia indicates any form of inadequate oxygen delivery to the brain, including hypoxemia and ischemia. Anoxic brain injury is extremely complex in nature and consists of a variety of insults to cells that involve decreased oxygen availability, systemic acidosis, hypercapnia, and sometimes superimposed ischemia. Other organs, such as the kidney and heart, can tolerate ischemic periods of up to thirty minutes, but the brain can tolerate no more than a few minutes of anoxia. Neurons survive only for minutes after the oxygen supply is reduced below critical levels. Pyramidal cells in the hippocampus, Purkinje cells of the cerebellum, and pyramidal cells of the third and fifth layers of the cerebral cortex are vulnerable to even moderate degrees of anoxia. Widespread necrosis of the cortex with the brainstem intact produces a vegetative state. More profound anoxia affecting the cortex, basal ganglia, and brainstem results in coma and subsequent death. Brief episodes of cerebral anoxia are usually well tolerated with patients escaping any irreversible deficits. Yet, an amnestic syndrome may follow transient periods of global ischemia with patients experiencing a severe antegrade amnesia and variable retrograde memory loss. Given the range of neurological disabilities that can ensue during ischemic brain injury, studies that determine the cellular mechanisms responsible for preserving both neuronal and vascular survival are essential for the development of viable therapeutics for this field. With this goal in mind, this issue of Current Neurovascular Research offers a unique perspective into not only some of the potential cellular mechanisms responsible for injury to the brain, but also the temporal parameters that appear to be intimately linked to a cells fate. The ability to identify the temporal cellular determinants of clinical deterioration in the nervous system could bring new insight into unexplained clinical deterioration. For example, individuals with anoxic-ischemic coma of approximately six hours duration, but with unremarkable insults on brain imaging, can sometimes suffer from permanent cognitive deficits. In addition, delayed neurologic deterioration following only a brief injury to the nervous system also can ensue that includes neuropsychological impairment or unconsciousness. In their original article, He et al. illustrate that aged animals may be less susceptible to ischemic cerebral injury, but these aged animals unfortunately lose their innate ability to respond to protective measures such as ischemic preconditioning which can reduce cerebral infarct size in young animals. This significantly reduced protection normally afforded by ischemic preconditioning in young animals was markedly reduced in aged counterparts and may be associated with a reduction in expression of the N-methyl-D-aspartic acid receptor 1 as well as modified tolerance to caspase mediated cell death mechanisms. Overall, the study sheds new light on some of the temporal parameters that can determine clinical disability following cerebral ischemia and the multiple variables that need to be addressed to achieve broad clinical efficacy for both young and more senior individuals. In our next original article, Okouchi et al. follow suit with the lead article in regards to the temporal parameters that can influence cell survival by showing that chronic hyperglycemia as well as acute glucose reduction from a chronic hyperglycemic state can contribute to cellular oxidative stress. Their work has implications for a number of disease states, including diabetes and Alzheimers disease. The authors demonstrate that chronic hyperglycemia was able to intensify methylglyoxal apoptotic cell injury and was associated with several intracellular processes that included mitochondrial redox balance, impaired glucose 6-phosphate dehydrogenase activity, and enhanced basal expression of apoptosis protease activator factor-1. Chong et al. in their original work provide important evidence that novel neuroprotective strategies, such as the administration of erythropoietin, are also critically related to the temporal modulation of intracellular apoptotic pathways. These investigators show that erythropoietin prevents neuronal β-amyloid toxicity, but that protection requires the early translocation of nuclear factor-κB from the cytosol to the nucleus to initiate an anti-apoptotic program. Without this intracellular translocation of nuclear factor-κB within a tight six hour period following β- amyloid toxicity, such as during experiments that employ the gene silencing of nuclear factor-κB, neuroprotection by erythropoietin is lost. Although the original work by Laidley et al. does not focus upon specific cellular mechanisms of ischemic cell injury, the study by these investigators presents an important analysis of the use of experimental animal models to yield scientifically sound data that can approximate clinical disease. The authors examine the use of a popular animal model for forebrain ischemia, namely the Mongolian gerbil (Meriones unguiculatus). Their work provides us with a refreshing perspective on both the benefits of this model for cerebral ischemia, but also the limitations of current commercially available strains and the considerations that should come into play for robust data analysis with this model. Our three review articles for this issue of Current Neurovascular Research complement the original articles by providing a broader overview of several of the cellular mechanisms that can contribute to the temporal determinants of cellular protection and plasticity. Han and Suk provide a thorough discussion of the neurovascular unit and the crosstalk that can occur between endothelial cells and microglia during inflammatory disorders of the nervous system. In particular, their review addresses the timely modulation required of the blood brain barrier, chemokines, and microglia for effective therapeutic strategies against neurodegenerative disease. Maiese et al. lead us into the intricate world of specific class of G-protein-linked receptors known as metabotropic glutamate receptors and their interesting role during a variety of disorders that can include amyotrophic lateral sclerosis, Parkinsons disease, Alzheimers disease, epilepsy, trauma, and stroke. The authors highlight the complexity of the metabotropic glutamate receptors in the nervous system. These receptors can control several cellular systems that involve neuronal, vascular, and inflammatory pathways, but function at times as a double edge sword that can either promote or prevent cellular function. Our final article by Dhanasekaran and Ren focuses upon the unique role of coenzyme Q, a ubiquitous protein in both plants and animals, that can play a vital role during neurodegenerative disease, cardiovascular disorders, and oxidative stress, such as during diabetes. In humans, coenzyme Q-10 is the predominant form and offers the advantages of being a lipid-soluble antioxidant that can rapidly alter cellular redox mechanisms, energy reserves, and stabilize mitochondrial membrane potential to control "time sensitive" pathways that may precipitate cellular injury. As our knowledge of basic cellular injury mechanisms continues to grow from the original work of Lavoisier and Barcroft, this issue of Current Neurovascular Research allows us to become increasingly more cognizant with the notion that "timing is everything" at both the cellular and clinical levels to effectively treat a broad spectrum of individuals afflicted by any disease entity.