Inactivation of tumor suppressor gene is a key event in carcinogenesis. p53 is one of the most important tumor suppressor genes in the genome, and its mutations are found in approximately 50% of human cancers. p53 mutation is also the main cause for human Li-Fraumeni syndrome. The vast majority of p53 mutations are missense mutations, and the corresponding mutant p53 proteins not only lose wild-type p53 tumor suppressor activities, but also gain new oncogenic properties favoring cancer development. Here, we mainly discussed the structural and functional alterations of mutant p53, the molecular mechanisms underlying gain of oncogenic functions, and the strategies and explorations of suppressing mutant p53 activities.