Abstract: The protein p53 plays an important role in the regulation of DNA repair, cell cycle arrest, apoptosis, senescence, autophagy and metabolism. MDM2 and MDM4 are the key negative regulatory proteins of p53. Inhibition of MDM2 and MDM4 has become a research hotspot in cancer therapy. Currently, seven MDM2 inhibitors(RG7112, MI-77301, RG7388, AMG232, CGM097, MK-8242, DS-3032b)and one MDM2/MDM4 dual inhibitor(ALRN-6924)have entered clinical trials. This paper highlights small molecule discovery, pharmacological activities and clinical research advances of MDM2 inhibitors in clinical trials, in addition, this review introduces research advances of MDM2/MDM4 dual inhibitors.