Systemic sclerosis is a multifactorial and heterogeneous disease. Genetic and environmental factors are known to interplay in the onset and progression of systemic sclerosis. Sex plays an important and determinant role in the development of such a disorder. Systemic sclerosis shows a significant female preponderance. However, the reason for this female preponderance is incompletely understood. Hormonal status, genetic and epigenetic differences, and lifestyle have been considered in order to explain female preponderance in systemic sclerosis. Sex chromosomes play a determinant role in contributing to systemic sclerosis onset and progression, as well as in its sex-biased prevalence. It is known, in fact, that X chromosome contains many sex- and immuno-related genes, thus contributing to immuno tolerance and sex hormone status. This review focuses mainly on the recent progress on epigenetic mechanisms--exclusively linked to the X chromosome--which would contribute to the development of systemic sclerosis. Furthermore, we report also some hypotheses (dealing with skewed X chromosome inactivation, X gene reactivation, acquired monosomy) that have been proposed in order to justify the female preponderance in autoimmune diseases. However, despite the intensive efforts in elucidating the mechanisms involved in the pathogenesis of systemic sclerosis, many questions remain still unanswered.