This review highlights our current understanding of the biology of, survival of, and transgene expression by genetically modified fibroblasts (GMFb) carrying stably integrated transgenes in vivo. Experimental data demonstrate that three elements will enhance expression by and survival of GMFb in vivo: a matrix scaffolding to take the place of the existing dermis, the presence of elements of the extracellular matrix in the construct used to move GMFb to the in vivo setting, and the utilization of immortalized fibroblasts to carry the transgenes. Although moving GMFb to an in vivo setting is an invasive procedure, there are a number of clinical settings where GMFb appear to be the suitable cell for gene therapy.