Y-box binding protein is a group of proteins that exist in a wide range, from low level to high level, of biologic species and they perform multiple biological functions. Numerous researches indicate that YB-1, as a member of the Y-box binding protein family, can interact with many important biological molecules and significantly influence the physiological function in organisms. More importantly, YB-1 also has a very profound role in relation to many diseases, especially to occurrence and development of cancer, and it can induce and maintain all the phenotypes and multiple drug resistance (MDR) of cancer cells. It is anticipated that a novel strategy of cancer treatment targeting YB-1 will effectively slow down the conditional deterioration and abrogate MDR in the cancer patients. The current progresses made in the YB-1 researches to its association with the occurrence/development of cancer were discussed and prospect on new strategies targeting YB-1 was provided.