Abstract: p53 is a critical tumor suppressor, and certain cancer cells gain a growth advantage by overexpressing its negative regulator, murine double minute 2(MDM2), which degrades p53. Small-molecule drugs blocking the MDM2-p53 interaction not only stabilize p53, but also release its anticancer functions, halting cell cycle progression and inducing cell apoptosis. This paper summarizes 13 clinical drugs targeting the MDM2-p53 interaction, and highlights their latest clinical research progress, the challenges they face, and future opportunities. Additionally, the paper reviews new developments in drug discovery related to the MDM2-p53 axis, discussing how innovative technologies and methods have introduced novel drug models and clinical candidates, and how these approaches activate p53 from new perspectives for cancer therapy.