The p53-related protein p63 has pleiotropic functions, including cell proliferation, survival, apoptosis, differentiation, senescence, and aging. The p63 gene is expressed as multiple isoforms that either contain an N-terminal p53-homologous transactivation domain (TAp63) or that lack this domain (ΔNp63). Multiple studies have demonstrated that p63 plays a crucial role in stratified epithelial development, and have shown the importance of p63 for maintaining proliferation potential, inducing differentiation, and preventing senescence. Additionally, much research focuses on the role of p63 in cancer progression. Clinical evidence suggests that p63 may play a role in inhibiting metastasis. Similarly, genetic mice models together with cell culture data strongly indicate that p63 deficiency may be a causative factor for metastatic spread. Moreover, the role of p63 in cancer metastasis has been shown to be greatly related to the ability of mutant p53 to promote cancer malignancy. However, there is still much confusion as to what the role of each specific isoform is. In this review, we highlight some of the major findings in the current literature regarding the role of specific p63 isoforms in development, tumorigenesis, and particularly in cancer metastasis.