Inborn errors of metabolism (IEMs) are a large group of genetic disorders, mostly occurring in the pediatric population, caused by single-gene defects impairing a metabolic pathway. Despite their monogenetic nature, establishing clear-cut genotype/phenotype correlations has proved difficult and discordant phenotypes among patients sharing the same genotype, even in monozygotic twins, have been described. There is increasing evidence that in several IEMs, including lysosomal storage disorders, phenylketonuria, and Wilson disease, the influence of epigenetics on clinical heterogeneity, pathophysiology, and prognosis is significant. Epigenetics is known to play a causative role in epi-cblC, which has not been described in other IEMs, up to now. Epi-cblC is a specific IEM which is caused by digenic epimutations in the MMACHC and TESK2 promoters triggered by transcriptional interference arising from splicing variants in the adjacent PRDX1 gene. Comprehension of the epigenetic mechanisms involved in IEMs could facilitate treatment monitoring and provide new therapeutic opportunities.