The transcription factor p63 is commonly over-expressed in squamous cell carcinomas of the head and neck (SCCHN). By microarray analysis of p63-siRNA-treated SCCHN cells we identified 127 genes whose expression relies on over-expression of p63. More than 20% of these genes are involved in cell motility. Chromatin immunoprecipitation and reporter assay revealed PAI-1 and AQP3 as direct p63 transcriptional targets. In addition to PAI-1, most of the key cell motility-related molecules are up-regulated by p63, such as MMP14 and LGALS1. Our findings indicate a contribution by p63 in cell invasion and migration, supporting an oncogenic role for p63 in SCCHN.