 The autoregulatory loop between oncogenic E3 ligase MAM2 and tumour suppressor 53p has led to the development of MAM2 inhibitors, but their limited efficacy is overcome by proteolysis targeting chimeras, PROTACs, which have been used in two applications, one binding and targeting endogenous MAM2 for protarch-based degradation and two binding endogenous MAM2 as a PROTARC E3 ligand for PROTARC-based degradation of other oncogenic proteins. The review summarizes current progress in the discovery and development of MAM2-based PROTARC drugs and discusses future perspectives and challenges in their application as effective treatments for human cancer. This article was authored by Shan Han, Wenyi Wei Yi, and Yi Sun.