Recent findings have shown that the development of teeth involves a complex sequence of molecular events in which the p53 family member p63 is involved. Indeed, mice lacking p63 do not have teeth and humans bearing mutations in p63 suffer developmental syndromes that affect tooth morphology and number. Several isoforms of p63 have been described: the use of two different promoters produces longer TAp63 isoforms, or shorter, 5' truncated isoforms known as ΔNp63. The 3' end of primary transcripts is then subject to alternative splicing resulting in three additional isoforms: alpha (α), beta (β) and gamma (γ). Tooth development relies mainly on the activity of the N-terminally truncated ΔNp63 isoforms. Here we review the experimental evidence for the involvement of ΔNp63 in tooth development through its ability to sustain the molecular signalling that orchestrates epithelial-mesenchymal interaction.