The human p63 gene codes for multiple protein isoforms and is commonly over-expressed in squamous cell carcinoma of head and neck (SCCHN). This expression is predominantly of the DeltaN- and beta-isoforms, the former lacking the p53-related transactivation domain. p63 can activate or repress transcription of p53 and p73 target genes, but also has unique transcriptional targets and, unlike other p53 family members, is required for normal development and differentiation of squamous epithelia. We have identified novel targets of p63, using microarray analysis of SCCHN cells that stably over-express individual DeltaNp63 isoforms. All three isoforms induced expression of the cancer stem cell marker, CD44, with the DeltaNp63beta isoform showing strongest induction. Using chromatin immunoprecipitation, we were unable to show direct binding of p63 to the CD44 promoter, but found that p63 specifically increased expression of CD44 lacking variant exon 2. Each of the DeltaNp63 isoforms up-regulated expression of keratins 6A and 14 and down-regulated expression of keratins 4 and 19, in keeping with their expression patterns in SCCHN. The data strengthen the idea that p63 has key roles in regulating normal and abnormal differentiation processes through both induction and repression of genes with opposite functions. The identification of up-regulation and differential splicing of CD44 following p63 over-expression indicates roles in the regulation of adhesion, metastasis and the cancer stem cell phenotype.