Tumor multidrug-resistant(MDR) reverters inhibit the function of drug transporters and thus reverse MDR. In contrast,anti-MDR agents circumvent tumor MDR by directly inhibiting or killing MDR tumor. In recent years, the development of novel anti-MDR agents has become a major focus of research. This review summarized the advances in MDR mechanisms concentrating on the relationships between P-glycoprotein and apoptotic regulation and between ceramide signal system and MDR. With this understanding, the authors classified anti-MDR agents for the first time as agents which are structurally modified from MDR-related drugs, disrupt MDR mechanisms, induce caspase-independent apoptosis, interfere with ceramide metabolism, and are mechanism-unknown. Meanwhile, their mechanisms and major features of actions were also discussed.