As CDKN2A loss, MDM2 overexpression, and p53 inactivation are the main events for tumor progression to high-risk GISTs, in this article, we review previous reports regarding p53 in GIST and propose a novel treatment strategy against GIST by non-genotoxic targeted activation of p53. The gene discussed is CDKN2A; the disease is gastrointestinal stromal tumor.