p63 is a member of the p53 tumor suppressor family that is critical for epithelial differentiation and also has an important role in cancer progression. Currently, the molecular mechanisms governing regulation of p63 function remain largely unclear. This study identifies a unique E3 ubiquitin ligase for p63, SCFβTrCP1. SCFβTrCP1 is able to bind p63γ isoforms, with a higher affinity for the TAp63γ isoform. Strikingly, co-expression of TAp63γ and βTrCP1 leads to the stabilization of TAp63γ. This stabilization of TAp63γ leads to up-regulation of p21 at the mRNA and protein level by increased binding of TAp63γ at the p21 promoter. The up-regulation of p21 causes a subsequent increase in G1 phase cell cycle arrest. Last, SCFβTrCP1 is able to ubiquitylate TAp63γ, and this ubiquitylation, as well as the increased activity of TAp63γ, is ablated with the expression of a ubiquitin-deficient mutant of βTrCP1 (ΔFβTrCP1). Therefore, our study reveals that SCF βTrCP1 is an E3 ligase that activates p63 through ubiquitylation.