Fibroblasts have come a long way to be eventually recognized as a most complex cell type of diverse lineage origins and of performing a multitude of functions in healthy and diseased organs (Driskell and Watt 2015; LeBleu and Neilson 2020; Torregrossa et al. 2025; Vorstandlechner et al. 2020). Here, Pfeiferová and colleagues (2025) report studies on HOX gene expression from normal and cancer-associated human fibroblasts (CAFs) of diverse origin. Specifically, adult facial fibroblasts derived from the ectomesenchyme, and upper forearm skin fibroblasts of mesodermal origin were investigated. In addition, CAFs derived from a variety of tumor types and their metastases, grown either in ectomesenchyme- or mesoderm-derived body regions, were analyzed. The authors performed transcriptome profiling on microarrays or by RNA-seq, and immunocytochemistry. To begin with, they did not observe significant differences of the cell volume and the Ki-67-based growth kinetics between adult facial and forearm skin fibroblasts. Moreover, they were unable to detect HOX genes in adult facial fibroblasts as was reported earlier for avian embryos (Creuzet et al. 2005). In contrast, the HOXA9, HOXD9, HOXA10, HOXD10, HOXA11, HOXD11, HOXA13, and TBX5 genes were strongly expressed in adult forearm fibroblasts. Immunocytochemical detection of HOXC6, HOXC8, HOXD10, TBX4, and TBX5 protein was basically confirmatory of these results. No general difference in homeobox gene expression could be verified in samples of fibroblasts originating from female or male adults. In CAFs stemming from malignant tumors and their metastases grown in mesoderm-derived body regions, the HOX gene expression pattern of normal fibroblasts was maintained, and in those of ectomesenchyme-derived body regions HOX gene expression was not detectable. In summary, and to cite the authors “the data confirm the conservation of the HOX code in normal and CAFs isolated from a broad panel of tissues and cancer types in adults, including skin, oral mucosa, skin cancers (basal cell carcinoma, squamous cell carcinoma, melanoma), non-tumorous pancreatic tissue from patients with pancreatic cancer, pancreatic ductal adenocarcinoma, brain tissue and malignant brain tumors (glioblastoma and brain metastases).” They also conclude that local fibroblasts predominantly serve as the source of CAFs in almost all samples evaluated. Last but not least, they emphasize the importance that the embryonic lineage origin of fibroblasts must be considered in biomedical research.