Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vascular injury, activation of the immune system, and diffuse tissue fibrosis. The precise etiology of SSc is undetermined, but there is evidence suggestive of a connection between environmental factors and SSc pathogenesis. In general, harmful environmental factors are sensed by the epigenetic regulatory mechanisms that alter host gene expression leading to the emergence of disease-specific phenotype. There are three epigenetic mechanisms involved in gene regulation: DNA methylation, histone modifications, and microRNAs. Although there is evidence that SSc phenotype could be, to a some degree, determined by genetic variants, it is clear now that non-genetic factors outweigh the genetic risk in SSc. Accordingly, the environment can trigger epigenetic regulation that in turn establishes a molecular framework linking environmental exposures to genetics, leading to the disease process, possibly in a genetically predisposed host. Although we have just begun to appreciate the potential role of epigenetics in SSc, many important and promising clues have been observed. In this review, we will summarize the work that has been done in the field of epigenetic regulation in SSc, and we will discuss possible factors and mechanisms that may lead to epigenetic dysregulation in SSc.