There is growing evidence that implicates epigenetic modification in the pathogenesis of systemic sclerosis (SSc). The complexity of epigenetic regulation and its dynamic nature complicate the investigation of its role in the disease. We will review the current literature for factors that link epigenetics to SSc by discussing DNA methylation, histone acetylation and methylation, and non-coding RNAs (ncRNAs), particularly microRNA changes in endothelial cells, fibroblasts (FBs), and lymphocytes. These three cell types are significantly involved in the early stages and throughout the course of the disease and are particularly vulnerable to epigenetic regulation. The pathogenesis of SSc is likely related to modifications of the epigenome by environmental signals in individuals with a specific genetic makeup. The epigenome is an attractive therapeutic target; however, successful epigenetics-based treatments require a better understanding of the molecular mechanisms controlling the epigenome and its alteration in the disease.