The pathogenesis of systemic sclerosis (SSc) has been intensely investigated, and the scientific community is unravelling a detailed dissection of the molecular pathways leading to the fibrotic process. Additionally, a wealth of brilliant in vivo studies on several animal models has shown the capacity of several drugs to temper the fibrotic process. However, to date, the translation of these data in the clinic with interventional studies failed to demonstrate any consistent efficacy in ameliorating tissue fibrosis or modifying the evolution of SSc. The discrepancy between the extremely promising in vitro and in vivo results, and the otherwise disappointing results of clinical studies is striking, and it is now inevitably dampening the enthusiasm on the potentially direct translation of research into clinical progress. Moreover, it is pushing the community to raise an increasing number of doubts on the use of the current preclinical models. The studies on the use of tyrosine kinase inhibitors (TKI) nilotinib and imatinib for skin fibrosis are a clear example of the contrast between extremely promising in vitro and in vivo data, and the poor data obtained in the clinical setting. Indeed, in vitro data on TGF-β and PDGF signalling have built a strong rationale for the use of TKI as antifibrotic agents in SSc.1 ,2 Furthermore, extensive in vivo studies on bleomycin-treated mice and TSK mice, widely used animal models of SSc, showed brilliant results of nilotinib and imatinib in preventing skin fibrosis and improving fibrosis in different organs.3 Unfortunately, both TKIs failed to demonstrate consistent clinical results in SSc patients in open label and controlled trials.4 ,5 An interesting manuscript from Maurer et al , published in the December issue of Ann Rheum Dis , describes the effort to understand the reasons of this discrepancy …