Systemic sclerosis is a complex autoimmune disease with widespread fibrosis in skin and internal organs, microvasculopathy, and autoantibodies. The disease causes ischemic changes and leads to impairment of internal organs with reduced quality of life and life expectancy. The pathogenesis is not clearly known but involves adaptive and innate immune cells which infiltrate skin lesions mostly early in the disease process. Current treatment is based on immunosuppressives, but there is a significant unmet therapeutic need, and a new therapeutic approach is required. Autologous haematopoietic stem cell transplantation appears to be an effective therapeutic option for SSc but requires standardization to reduce transplant-related mortality and post-transplant adverse effects. Mesenchymal stem cells (MSCs), exerting immunosuppressive, antifibrotic, and angiogenic actions, appear to be a promising therapeutic option but require further refinement. MSC-derived microvesicles retain MSC functions and circumvent some of the MSC challenges and thus may provide a more favorable therapeutic approach. Key Points • There are unmet therapeutic needs for systemic sclerosis. • Autologous haematopoietic stem cell transplantation is an effective therapeutic option but needs standarization. • Mesenchymal stem cells are a promising therapeutic option but requires refinement.