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Systemic sclerosis (SSc) is a multifaceted connective tissue disease characterized by widespread vasculopathy and autoimmune reactions that evolve into progressive interstitial, perivascular, and vessel wall fibrosis that affects the skin and multiple internal organs. Such an uncontrolled fibrotic process gradually disrupts the physiologic architecture of the affected tissues and frequently leads to significant organ dysfunction, thus representing a major cause of death in SSc patients. The main fibrosis orchestrators in SSc are represented by chronically activated myofibroblasts, a peculiar population of mesenchymal cells combining the extracellular matrix-synthesizing features of fibroblasts with cytoskeletal characteristics of contractile smooth muscle cells. Multiple lines of evidence support the notion that profibrotic myofibroblasts may derive not only from the activation of tissue resident fibroblasts but also from a variety of additional cell types, including pericytes, epithelial cells, vascular endothelial cells and preadipocytes/adipocytes. Here we overview an emerging picture that espouses that several cell transitional processes may be novel essential contributors to the pool of profibrotic myofibroblasts in SSc, potentially representing new suitable targets for therapeutic purposes. An in-depth dissection of the multiple origins of myofibroblasts and the underlying molecular mechanisms may be crucial in the process of deciphering the cellular bases of fibrosis persistence and refractoriness to the treatment and, therefore, may help in developing more effective and personalized therapeutic opportunities for SSc patients.