Systemic Sclerosis (SSc) is a clinically complex and rare autoimmune connective tissue disease of which management is challenged by difficulties in establishing an early/accurate diagnosis and a lack of FDA-approved agents that target its underlying pathology. Consequently, current practice is primarily focused on treating SSc-related complications. However, advances in understanding SSc pathophysiology have identified potential disease-modifying therapies that target select cellular and profibrotic pathways. These include agents that target cytokines such as interleukin-6 (IL-6), lipid mediators such as lysophosphatidic acid receptor (LPA1), B-lymphocyte surface antigens such as CD20, transforming growth factor (TGF)-β, and multiple tyrosine kinases (TKs). Thus, this session will focus on strategies to aid early recognition of SSc, the underlying pathophysiology of SSc and potential treatment targets, and current treatment recommendations for SSc-related multi-organ complications. Further, the latest evidence with regards to emerging, late-stage, targeted therapies for the treatment of SSc will be presented. Lastly, strategies that ensure evidence-driven clinical decision-making that supports coordinated and cooperative medical management among disciplines will be explored.