Systemic sclerosis (SSc) is an autoimmune fibrotic disease of unknown aetiology that is characterized by vascular changes in the skin and visceral organs. Autologous haematopoietic stem cell transplantation can improve skin and organ fibrosis in patients with progressive disease and a high risk of organ failure, indicating that cells originating in the bone marrow are important contributors to the pathogenesis of SSc. Animal studies also indicate a pivotal function of myeloid cells in the development of fibrosis leading to changes in the tissue architecture and dysfunction in multiple organs such as the heart, lungs, liver and kidney. In this Review, we summarize current knowledge about the function of myeloid cells in fibrogenesis that occurs in patients with SSc. Targeted therapies currently in clinical studies for SSc might affect myeloid cell-related pathways. Therefore, myeloid cells might be used as cellular biomarkers of disease through the application of high-dimensional techniques such as mass cytometry and single-cell RNA sequencing.