In recent years, the principal mechanisms underlying the formation and consequent accumulation of profibrotic myofibroblasts in SSc have been investigated in depth, leading to the discovery of different molecular pathways (i.e., TGF-β and ET-1 cascade, developmental pathways and JAK/STAT signaling), against which several antifibrotic agents have been tested in preclinical models or are currently under evaluation in different clinical trials. This evidence concerns the gene TGFB1 and systemic sclerosis.