Accumulation of mutant p53 has been recognized as an important factor that promotes cancer progression and metastasis. Thus, strategies that promote the degradation of mutant p53 might be beneficial for the treatment of cancers. In a recent issue of Genes & Development, Vakifahmetoglu-Norberg et al. demonstrate that blocking autophagy may lead to the degradation of mutant p53 through activating chaperone mediated autophagy, a lysosomal dependent degradation mechanism. This research provides a new mechanism by which mutant p53 might be degraded and the possibility of activating chaperone mediated autophagy as a new treatment for cancers with mutant p53.