1 2 3 K m 4 1 5 + + + + 6 7 8 10 11 12 13 14 15 2 Fig. 1 N d +  Fig. 2 1 + + 2 2+ 2+ 3 4 5 6 2+ 7 2+ 2+ 2+  16 17 18 19 20 21 22 23 24 3 3 Fig. 3 a b c  25 27 27 28 29 4 30 31 25 32 33 34 32 Fig. 4 ETC 1 2 TCA 3 4 5 6  31 4 35 25 31 36 39 35 35 40 41 42 43 44 45 49 50 51 52 53 54 55 56 56 5 57 59 5 Fig. 5 Adaptation to hypoxia-cell fate and beyond. Expression of HIF in neurons leads to the constitutive expression of proteins associated with cell death (BNIP3, NIX, and PUMA) and cell survival (VEGF, glycolytic enzymes, Epo, and p21 waf1/cip1). Similar prodeath gene expression is found in neurons exposed to hypoxia or hypoxia mimetics despite the absence of cell death. It appears the oxygen “starved” neurons have stepped to the edge of the cliff. If during the ensuing hours to days the neuron becomes acidotic or oxidized, then prodeath proteins such as BNIP3 undergo a conformational change, insertion into the mitochondrial membrane, release of apoptotic effectors, and death. By contrast, if the survival genes are effective in neutralizing the hypoxic stress (e.g., no acidosis or oxidative stress), then the death genes never get activated. Our studies indicate that antioxidants, short interfering RNAs to BNIP3 or inhibitors of the HIF prolyl 4 hydroxylases tip the balance toward survival (away from the cliff)  The model has some clear predictions. First, low molecular weight global inhibitors of the HIF prolyl 4 hydroxylases will be more effective at preventing injury and repairing damage after stroke than selective isoform inhibitors. These inhibitors will engage HIF-dependent and HIF-independent pathways at cellular, local, and systemic levels and ultimately alleviate the discrepancy in nutrient supply and demand. They can also (via mechanisms that are only beginning to be defined) divert HIF away from its tendencies as a prodeath transcription factor. The ability of single “drugs” to target an oligopoly of proteins (HIF PHD1–3) to affect a concerted program of neuroprotection involving more than 70 genes and larger number of proteins suggests a strategy for overcoming the heterogeneity inherent in stroke pathophysiology in the short term. While a significant amount of work needs to be done to adequately assess the viability of this strategy for human therapeutics, the notion of augmenting endogenous adaptive programs via HIF PHDs to thwart disease continues to gain currency.