p63, a homologue of the transcription factor p53, is essential for maintaining the proliferative capacity of epithelial stem cells. The p63 gene yields two major isoforms transcribed from dual promoters and at least three different splice variants at its carboxy-terminus. The TAp63γ isoform functions as a p53- like tumor suppressor and transactivates p53 gene targets. In contrast, ΔNp63α predominates in epithelial stem cells and regulates their proliferative potential, whilst also acting as an oncogene by suppressing the function of both p53 and TAp63γ in a dominant-negative manner. Frequent upregulation of ΔNp63α has been reported in human epithelial cancers and suggests a role in tumorigenesis, though the molecular mechanisms of its aberrant activity are unclear. Our prior studies found specific expression in squamous cell carcinomas of an aberrantly spliced ΔNp63α isoform lacking exon 4-coded sequences (the Δ4 isoform). Further assessment of gene expression and protein binding by DNA microarray and ChIP-seq respectively identified gene candidates with expression patterns unique to this aberrant isoform and with relevance to cell cycle control, inflammation, and apoptosis. Our data show that mice carrying a heterozygous allele of the Δ4 isoform show an increased susceptibility to tumorigenesis, suggesting that dysregulation of p63 splicing may link stem cells to cancer. We will discuss our ongoing effort elucidating the potential involvement of this aberrantly spliced p63 isoform in the disruption of stem cell regulatory gene programs during cancer development of epithelia.