The current paradigm is that smooth muscle cells (SMCs) can adopt various phenotypes in atherosclerotic lesions, including a pro-inflammatory macrophage-like phenotype that might promote plaque rupture. A new study using single-cell RNA sequencing now shows that rather than assuming multiple phenotypes, SMCs transform almost exclusively into fibroblast-like cells (termed fibromyocytes) in atherosclerotic lesions in vivo in both humans and mice. This fibromyocyte phenotype is promoted by the expression of TCF21, a gene that has been causally associated with coronary artery disease (CAD). SMC-specific Tcf21 deletion in Apoe–/– mice markedly reduced SMC transition to fibromyocytes, leading to thinner fibrous caps. TCF21-expressing fibromyocytes were also present in human atherosclerotic lesions, and lower TCF21 levels in SMCs were associated with a higher risk of CAD. “These data suggest that both TCF21 expression and SMC phenotypic modulation are beneficial during the disease process,” conclude the authors.