Mitochondrial dysfunction can be triggered by various genetic and environmental factors, leading to a broad range of diseases. To study pathways that might protect from mitochondrial damage, Jain et al. performed a CRISPR–Cas9-mediated knockout of ~18,000 genes, revealing that deletion of a suppressor of the cellular response to low oxygen (hypoxia) significantly improved growth of cells with dysfunctional mitochondria. This suggested that the hypoxic response protects cells from defects resulting from mitochondrial malfunction. Indeed, it was demonstrated both in vitro and in vivo in the zebrafish that raising the hypoxic response through suppression of the inhibitory pathway improved survival when mitochondrial respiration was perturbed. The authors also showed that exposure to a hypoxic environment prevented cellular malfunctioning, alleviated disease symptoms and extended the lifespan of mice suffering from mitochondrial dysfunction. The next exciting step would be to attempt to harness hypoxic response for clinical applications.