Systemic sclerosis (SSc) is a complex heterogeneous fibrotic autoimmune disease with an unknown exact etiology, and characterized by three hallmarks: fibrosis, vasculopathy, and immune dysfunction. Dendritic cells (DCs) are specialized cells in pathogen sensing with high potency of antigen presentation and capable of releasing mediators to shape the immune response. Altered DCs distributions and their impaired functions may account for their role in breaking the immune tolerance and driving inflammation in SSc, and the direct contribution of DCs in promoting endothelial dysfunction and fibrotic process has only begun to be understood. Plasmacytoid dendritic cells in particular have been implicated due to their high production of type I interferon as well as other cytokines and chemokines, including the pro-inflammatory and anti-angiogenic CXCL4. Furthermore, a deeper understanding of human and mouse DC biology has clarified their identification and function in different tissues, and novel DC subsets have only recently been discovered. In this review, we highlight key findings and recent advances exploring DC role in the pathogenesis of SSc and other related autoimmune diseases, and consideration of their potential use as targeted therapy in SSc.