Systemic sclerosis (SSc) is a prototypical inflammatory fibrotic disease involving inflammation, vascular abnormalities and fibrosis that primarily affect the skin and lungs. The aetiology of SSc is unknown and its pathogenesis is only partially understood. Of all the rheumatic diseases, SSc carries the highest all-cause mortality rate and represents an unmet medical need. A growing body of evidence implicates epigenetic aberrations in this intractable disease, including specific modifications affecting the three main cell types involved in SSc pathogenesis: immune cells, endothelial cells and fibroblasts. In this Review, we discuss the latest insights into the role of DNA methylation, histone modifications and non-coding RNAs in SSc and how these epigenetic alterations affect disease features. In particular, histone modifications have a role in the regulation of gene expression pertinent to activation of fibroblasts to myofibroblasts, governing their fate. DNA methyltransferases are crucial in disease pathogenesis by mediating methylation of DNA in specific promoters, regulating expression of specific pathways. We discuss targeting of these enzymes for therapeutic gain. Innovative epigenetic therapy could be targeted to treat the disease in a precision epigenetics approach.