Epigenetic mechanisms have been implicated in the pathogenesis of renal diseases, including acute kidney injury (AKI). Mar et al. now unravel the acetylation and methylation at histones that are associated with the transcription of key genes in AKI. Notably, histone modifications display a remarkable heterogeneity in ischemic and endotoxic AKI. Targeting epigenetic programs may offer novel strategies to protect kidneys from AKI and enhance kidney repair and recovery.