Basal-cell carcinoma (BCC), the most common neoplasm in humans, occurs in a variety of morphological presentations. The mechanisms of BCC development downstream of the initial genetic mutations are not well understood, and different BCC morphological presentations might exhibit distinct gene expression patterns. We investigated superficial (n=8), nodular (n=8), and morpheiform (n=7) BCCs using 21K cDNA microarrays. Global gene expression profiles between respective BCC subtypes, and as compared with normal skin (n=8), were statistically defined by significance analysis of microarrays (SAM). Thirty-seven genes were subsequently validated by quantitative reverse transcriptase-PCR analysis using an expanded set of 31 BCCs. Gene ontology analysis indicated that gene expression patterns of BCC subtypes in multiple biological processes showed significant variation, particularly in genes associated with the mitogen-activated protein kinase (MAPK) pathway. Notably, genes involved in response to DNA-damage stimulus were uniquely upregulated in morpheiform BCCs. Our results indicate a relative similarity in gene expression between nodular and superficial BCC subtypes. In contrast, morpheiform BCCs are more diverse, with gene expression patterns consistent with their more "invasive" phenotype. These data may help us understand the complex behavior of BCC subtypes and may eventually lead to new therapeutic strategies.