We examined the effect of hypoxic-ischemia and hypoxia versus normoxia on postnatal murine brain substrate transporter concentrations and function. We detected a transient increase in the neuronal brain glucose transporter isoform (GLUT 3) in response to hypoxic-ischemia following 4 hr of re-oxygenation. This increase was associated with no change in GLUT 1 (blood-brain barrier/glial isoform), monocarboxylate transporter isoforms 1 and 2, synapsin I (neuronal marker), or Bax (pro-apoptotic protein), but with a modest increase in Bcl-2 (anti-apoptotic mitochondrial protein) protein concentrations. At 24 hr of re-oxygenation the increase in GLUT 3 disappeared but was associated with a decline in Bcl-2 protein concentrations and the Bcl2:Bax ratio, an increase in caspase-3 enzyme activity (apoptotic effector enzyme), and extensive DNA fragmentation, which persisted later in time (48 hr) only in the hippocampus. Hypoxia alone in the absence of ischemia was associated with a transient but modest increase in GLUT 3 and synapsin I protein concentrations, which did not cause significant apoptosis and/or necrosis. Assessment of glucose transporter function by 2-deoxyglucose uptake using two distinct techniques, namely 1] positron emission tomography (PET) and 2] the modified Sokoloff's method, revealed a discrepancy due to glucose uptake by extracranial Harderian glands which masked the accurate detection of intracranial brain glucose uptake by PET scanning. The modified Sokoloff's method assessing 2-deoxyglucose uptake revealed that the transient increase in GLUT 3 was critical in protecting against a decline in brain glucose uptake. We conclude that hypoxic-ischemic brain injury is associated with transient compensatory changes targeted at protecting glucose delivery to fuel cellular energy metabolism, which then may delay the processes of apoptosis and cell necrosis.