Systemic sclerosis (SSc) is a rare, chronic connective tissue disease affecting the skin, vessels, musculoskeletal system, and internal organs. Despite advances in pharmacotherapy of organ manifestations and new knowledge about the pathogenesis of SSc, there is still no effective universal treatment of this serious disease. The aim of this chapter is to introduce traditional, most commonly used experimental animal models of SSc, clarify their basic pathological mechanism, describe their advantages and limitations, and outline their use in preclinical tests of potential therapeutic agents with subsequent clinical trials in patients with SSc. The existing models have already contributed significantly to preclinical testing of several available biological agents and small molecules, some of which achieved promising results in early clinical studies, and could provide better prospects for patients with this incurable disease.