Gene expression profiles were determined for 12 cutaneous squamous cell carcinomas (SCC) removed from sun-exposed sites on nonimmunosuppressed patients. Gene expression in each SCC was compared to that in sun-exposed skin from the same patient using the Affymetrix HGU133 2.0 PlusGeneChip. We identified 440 genes with increased expression in SCC and 738 with decreased expression; overall we identified a large number of small changes in gene expression rather than a few marked changes that distinguished SCC from sun-exposed skin. Analyzing this robust data set according to biofunctional pathways using DAVID, transcriptional control elements using oPOSSUM, and chromosomal location using GSEA suggested genetic and epigenetic mechanisms of gene expression regulation in SCC. Some altered patterns of gene expression in SCC were consistent with regulation of spatially separated genes by a number of developmentally important transcription factors (forkhead, HMG, and homeo factors) that negatively regulated gene expression and to a few factors that positively regulated expression (Creb-1, NFkappaB, RelA, and Sp-1). We also found that coordinately enhanced expression of epidermal differentiation complex genes on chromosome 1q21 was a hallmark of SCC. A novel finding in our study was enhanced expression of keratin 13 in SCC, a result validated by immunohistochemical staining of an SCC tumor tissue array.