This review discusses about the current knowledge about the role of the ET-1/H-Ras/ERK1/2 pathway in the fibrosis and vasculopathy, with particular emphasis on the regulation of this pathway in the fibrotic microenvironment, the molecular mechanisms, and signaling involved in its pro-fibrotic actions, as well as the contribution of ET-1/H-Ras/ERK1/2 pathway in SSc and focusing on potential therapeutic implication. This evidence concerns the gene MAPK3 and vascular disorder.