p63, a member of the p53 tumor suppressor family, is essential for the development of epidermis as well as other stratified epithelia. Collective evidence indicates that ΔNp63 proteins, the N-terminally deleted versions of p63, are essential for the proliferation and survival of stratified epithelial cells and squamous cell carcinoma cells. But in response to DNA damage, ΔNp63 proteins are quickly downregulated in part through protein degradation. To elucidate the mechanisms by which ΔNp63 proteins are maintained at relatively high levels in proliferating cells but destabilized in response to stress, we sought to identify p63 interactive proteins that regulate p63 stability. We found that Stxbp4 and RACK1, two scaffold proteins, play central roles in balancing ΔNp63 protein levels. While Stxbp4 functions to stabilize ΔNp63 proteins, RACK1 targets ΔNp63 for degradation. Under normal growth conditions, Stxbp4 is indispensable for maintaining high basal levels of ΔNp63 and preventing RACK1-mediated p63 degradation. Upon genotoxic stress, however, Stxbp4 itself is downregulated, correlating with ΔNp63 destabilization mediated in part by RACK1. Taken together, we have delineated key mechanisms that regulate ΔNp63 protein stability in vivo.