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Leukodystrophies are a class of rare heterogeneous disorders which affect the white matter of the brain, ultimately leading to a disruption in brain development and a damaging effect on cognitive, motor and social‐communicative development. These disorders present a great clinical heterogeneity, along with a phenotypic overlap and this could be partially due to contributions from environmental stimuli. It is in this context that there is a great need to investigate what other factors may contribute to both disease insurgence and phenotypical heterogeneity, and novel evidence are raising the attention toward the study of epigenetics and transcription mechanisms that can influence the disease phenotype beyond genetics. Modulation in the epigenetics machinery including histone modifications, DNA methylation and non‐coding RNAs dysregulation, could be crucial players in the development of these disorders, and moreover an aberrant RNA maturation process has been linked to leukodystrophies. Here, we provide an overview of these mechanisms hoping to supply a closer step toward the analysis of leukodystrophies not only as genetically determined but also with an added level of complexity where epigenetic dysregulation is of key relevance. This article is categorized under:Regulatory RNAs/RNAi/Riboswitches > Regulatory RNARNA in Disease and Development > RNA in DiseaseRNA in Disease and Development > RNA in Development Leukodystrophies are rare brain disorders affecting white matter, with a clinical diversity still to be explained. Beyond genetics, epigenetic factors like histone modifications, DNA methylation, and non‐coding RNA dysregulation, as well as aberrant RNA maturation, are emerging as crucial contributors to these disorders. Created with Biorender.com