Using transcriptomic signatures and the Xenopus embryo infection screen, we identified that the hypoxia pathway involving prolyl‐4 hydroxylase and HIF‐1α play key roles in modulating infection tolerance and showed that metal ion chelators and a prolyl‐4 hydroxylase inhibitor can act as potential inducers of an active tolerance response to infection. The gene discussed is HIF1A; the disease is infection.