This study investigates the connection between cellular metabolism and gene expression in embryonic cells, focusing on the role of histone lactylation. The authors found that lactylation, a post-translational modification of histones, is dynamically deposited in the genome of neural crest (NC) cells as they transition to a state of increased glycolysis. This process is crucial for epigenomic remodeling and the proper expression of developmental genes. Specifically, lactylation marks genomic regions of glycolytic tissues like the NC and pre-somitic mesoderm, promoting the accessibility of active enhancers and the activation of the NC gene regulatory network (GRN). Reducing lactylation levels by targeting lactate dehydrogenases leads to downregulation of NC genes and impaired cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by the involvement of transcription factors SOX9 and YAP/TEAD. These findings highlight an epigenetic mechanism that integrates cellular metabolism with GRNs, which are essential for embryonic development.This study investigates the connection between cellular metabolism and gene expression in embryonic cells, focusing on the role of histone lactylation. The authors found that lactylation, a post-translational modification of histones, is dynamically deposited in the genome of neural crest (NC) cells as they transition to a state of increased glycolysis. This process is crucial for epigenomic remodeling and the proper expression of developmental genes. Specifically, lactylation marks genomic regions of glycolytic tissues like the NC and pre-somitic mesoderm, promoting the accessibility of active enhancers and the activation of the NC gene regulatory network (GRN). Reducing lactylation levels by targeting lactate dehydrogenases leads to downregulation of NC genes and impaired cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by the involvement of transcription factors SOX9 and YAP/TEAD. These findings highlight an epigenetic mechanism that integrates cellular metabolism with GRNs, which are essential for embryonic development.