Noda et al. found that simultaneous downregulation of KLF5 and friend leukemia integration 1 (FLI1) is a molecular hallmark of systemic sclerosis (SSc) dermal fibroblasts, and mice with double heterozygous deficiency of KLF5 and FLI1 spontaneously developed tissue fibrosis, vasculopathy, B-cell activation, and autoantibody production, which are quite similar to those in SSc. Here, KLF5 is linked to vascular disorder.