This study investigates the diversity, topographic differentiation, and positional memory in human fibroblasts. Fibroblasts, the principal cells of stromal tissue, are traditionally considered a single cell type, but this research reveals that fibroblasts from different anatomical sites exhibit distinct gene expression patterns, suggesting they are distinct differentiated cell types. Using genome-wide gene expression profiling, the study shows that fibroblasts from different sites display unique transcriptional patterns, with genes involved in extracellular matrix synthesis, lipid metabolism, and cell signaling pathways being differentially expressed. These patterns are consistent with the phenotypic defects associated with certain genetic diseases, and adult fibroblasts maintain key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie positional memory in fibroblasts. The study also highlights the role of fibroblasts in tissue development and repair, as well as their involvement in immune and inflammatory responses. The topographic transcriptome of fibroblasts includes genes involved in cell migration, ECM synthesis, and signaling pathways, which are essential for tissue development and function. The study further shows that fibroblasts maintain topographic differentiation in vitro, indicating that this differentiation is cell autonomous or requires only paracrine factors from other similarly fated fibroblasts. The findings suggest that fibroblasts have a complex and specialized role in tissue development and function, and that their molecular "address code" provides a framework for understanding the biological specificity and regulatory complexity of these processes. The study also highlights the importance of using site-matched controls in genetic and biochemical studies of human and mouse mutants.This study investigates the diversity, topographic differentiation, and positional memory in human fibroblasts. Fibroblasts, the principal cells of stromal tissue, are traditionally considered a single cell type, but this research reveals that fibroblasts from different anatomical sites exhibit distinct gene expression patterns, suggesting they are distinct differentiated cell types. Using genome-wide gene expression profiling, the study shows that fibroblasts from different sites display unique transcriptional patterns, with genes involved in extracellular matrix synthesis, lipid metabolism, and cell signaling pathways being differentially expressed. These patterns are consistent with the phenotypic defects associated with certain genetic diseases, and adult fibroblasts maintain key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie positional memory in fibroblasts. The study also highlights the role of fibroblasts in tissue development and repair, as well as their involvement in immune and inflammatory responses. The topographic transcriptome of fibroblasts includes genes involved in cell migration, ECM synthesis, and signaling pathways, which are essential for tissue development and function. The study further shows that fibroblasts maintain topographic differentiation in vitro, indicating that this differentiation is cell autonomous or requires only paracrine factors from other similarly fated fibroblasts. The findings suggest that fibroblasts have a complex and specialized role in tissue development and function, and that their molecular "address code" provides a framework for understanding the biological specificity and regulatory complexity of these processes. The study also highlights the importance of using site-matched controls in genetic and biochemical studies of human and mouse mutants.