During seed maturation phase, seeds acquire desiccation tolerance (DT), which is the capacity to survive extreme dehydration, a drastic loss of water content to levels below 10%. This allows the dry seeds to be alive for a certain period of time until water imbibition followed by germination. Subsequently, the DT is lost with a developmental transition from germination to seedling. The seed maturation program is significantly affected by environmental stresses, however the timing of DT acquisition in developing Medicago truncatula seeds is robust under several stress conditions, indicating that the tolerance is an important trait for plant seeds and is genetically switched at specific times in the maturation program. Some of the DT-related genes in seeds are also known to be commonly implicated in desiccation of the vegetative part in resurrection plants, suggesting that the understanding of molecular switches that turn on DT intrinsicly in maturating seeds may contribute to improve drought stress tolerance in plants. However, our understanding of molecular mechanisms for acquisition of DT during seed maturation remains fragmentary, especially regarding the epigenetic factors. ​Here, we performed RNA-Seq of maturating seeds before and after the DT phase in Medicago and detected differentially expressed genes potentially involved in the DT process. These genes were then compared with previous DT-related transcriptome datasets and those commonly detected were redefined as DT-core genes, suggesting their essential roles in the cell survival during desiccation. A cluster enrichment of these DT-core genes was confirmed by Chromatin Immuno Precipitation followed by sequencing (ChIP-seq) of specific histone marks as well as Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq), suggesting that the expression of some DT-core genes is epigenetically controlled during seed maturation. The regulatory mechanism of DT-core gene expression known to be important for seed DT, such as genes related to the metabolism and signaling of the plant hormone abscisic acid will be also discussed.