INTRODUCTION: Systemic sclerosis (SSc) is a progressive autoimmune rheumatic disease with high morbidity and mortality and few effective treatment options. Increased biopharmaceutical investment in therapeutic development for rare diseases has created new opportunities for drug discovery in SSc. However, despite the increased pipeline activity in SSc, success rates remain dismally low. AREAS COVERED: This review describes the current state of therapeutic development in SSc with an in-depth coverage of cohort enrichment strategies, as well as a discussion of relevant ethical and feasibility concerns. This review also highlights lessons learned from phase 3 trials in SSc published within the last 5 years in PubMed, underscoring the impact of background therapy on SSc disease course during the trial period. Emerging clinical trial formats and endpoints are also explored. EXPERT OPINION: The authors present recommendations to innovate clinical trial design in SSc, which integrate evidence from recent clinical trial and observational cohort studies in SSc. With a focus on the use of external control arms, the application of adaptive trial design and the development of global disease activity measures, the authors outline practical and ethical solutions to design precise and efficient trials in SSc with a higher probability of success.