Among the earliest pathologic events in systemic sclerosis (SSc) is the infiltration of mononuclear cells into the skin lesion. This inflammatory cell infiltration precedes the development of fibrosis, suggesting an integral role for the presence of these cells in the fibrotic events observed in the lesion. However, immunosuppressive therapies that are effective in other autoimmune disease have not been successful in the treatment of SSc, making the clinical management of this disease very difficult. The aim of this paper is to review the latest findings regarding the activation and the functional polarization of T cells and their role in the pathogenesis of SSc. Furthermore, the potential role of B cells, a hitherto scantily investigated inflammatory cell in SSc, is discussed. Understanding the interplay between T and B cells, and the processes that promote the fibrotic cytokine pattern seen in these patients is of utmost importance for the development of effective therapies to treat the clinical complications.