Mdm2 is a well studied oncogene and has been reported to be closely related to chemoresistance in different manners. In this article, we discuss the current knowledge of mdm2’s function in drug resistance, the novel relationship between MDM2 and Akt phosphorylation, the role of Akt signaling pathway in epithelial-mesenchymal transition, and the positive correlation among MDM2, epithelial-mesenchymal transition and drug resistance. We propose a possible pathway by which MDM2 increases drug resistance through inducing epithelial-mesenchymal transition independent of p53. This pathway may play a significant role in the tumorigenesis and chemoresistance. By targeting MDM2, we can re-activate the function of p53, inhibit the epithelial-mesenchymal transition process and thus increase cancer cells sensitivity to chemotherapy. Thus, from p53-dependent and p53-independent aspects, it may present a better strategy for cancer treatment than targeting other genes.