Systemic sclerosis (SSc) is a rare chronic disease of unknown etiology characterized by vascular abnormalities and fibrosis involving the skin and internal organs, especially the gastrointestinal tract, lung, heart and kidneys. Although the disease was historically stratified according to the extent of skin involvement, more recent approaches place more emphasis on patterns and extent of internal organ involvement. Despite numerous clinical trials, disease-modifying treatment options are still limited resulting in persistent poor quality of life and high mortality. This review provides an overview of autoantibodies in SSc and novel approaches to stratify the disease into clinically actionable subsets.