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Tyrosine kinase inhibitors (TKIs) have emerged as a targeted therapy of interest for the treatment of systemic sclerosis (SSc). Recently, several groups have performed pilot or “proof-of-concept” studies to determine the feasibility of this approach for the treatment of the cutaneous and pulmonary manifestations of this multisystem disease. The conclusions drawn by these different studies have been conflicting, and some controversy has arisen as to whether tyrosine kinase inhibition is a treatment approach worthy of continued study. This paper summarizes this research to date with emphasis on the challenges in interpreting proof-of-concept studies in this patient group.