Keloids are benign dermal tumors that form during wound healing in genetically susceptible individuals. The mechanism(s) of keloid formation is unknown and there is no satisfactory treatment. We have reported differences between fibroblasts cultured from normal scars and keloids that include a pattern of glucocorticoid resistance and altered regulation of genes in several signaling pathways associated with fibrosis, including Wnt and IGF/IGF-binding protein 5 (IGFBP5). As previously reported for glucocorticoid resistance, decreased expression of the Wnt inhibitor secreted frizzled-related protein 1 (SFRP1), matrix metalloproteinase 3 (MMP3), and dermatopontin (DPT), and increased expression of IGFBP5 and jagged 1 (JAG1) are seen only in fibroblasts cultured from the keloid nodule. In vivo, decreased expression of SFRP1 and SFRP2 and increased expression of IGFBP5 proteins are observed only in proliferative keloid tissue. There is no consistent difference in the replicative life span of normal and keloid fibroblasts, and the altered response to hydrocortisone (HC) and differential regulation of a subset of genes in standard culture medium are maintained throughout at least 80% of the culture lifetime. Preliminary studies using ChIP–chip analysis, Trichostatin A, and 5-aza-2′-deoxycytidine further support an epigenetically altered program in keloid fibroblasts that includes an altered pattern of DNA methylation and histone acetylation.