Abstract Introduction and aims Keloids are fibroproliferative scars that progressively grow beyond the original wound site. They occur as a result of genetic, epigenetic and environmental abnormalities. Fibroblasts are best characterized for their role in depositing and remodelling the extracellular matrix (ECM) and are believed to have a crucial role in keloid formation. However, the detailed molecular signatures that promote this pathogenic phenotype are still unknown. Methods To investigate the epigenetic and genetic changes in keloid fibroblasts, we performed assay for transposase-accessible chromatin (ATAC)-Seq and RNA-Seq on a patient-matched set of keloid and normal fibroblasts. ATAC-Seq is a high-throughput sequencing method that defines chromatin accessible regions in which the binding of sites of transcription factors that regulate gene expression can be mapped. Identified candidates are validated in keloid fibroblasts via quantitative polymerase chain reaction and their functional role is analysed in various in vitro assays. Results ATAC-Seq analysis revealed more accessibility in coding regions of keloid fibroblasts compared with normal fibroblasts. Pathways enriched in these regions include transcriptional regulation, embryonic development, cell differentiation, calcium-binding and collagen remodelling. Intriguingly, several developmental epigenetic modulators were identified that may alter the transcription and chromatin landscape of keloid fibroblasts to a more plastic state and have the capacity to influence cell differentiation choices, potentially promoting chondrogenic and adipogenic cell features. Currently, we are investigating the ability of keloid fibroblasts to be more readily differentiated into other cell types including induced pluripotent stem cells, and the contribution of those candidates on fibrotic features to the cell are also being explored. Conclusions Our analysis reveals that the chromatin of keloid fibroblasts is more accessible, especially in genomic regions associated with embryonic development and keloid fibroblasts show an increased plasticity in vitro. These findings may support the development of fibroblast-targeted therapies for keloid scars and possibly other connective tissue disorders.