TP53, encoding p53, is one of the most famous tumor suppressor genes. The majority of human cancers demonstrate the inactivation of the p53 pathway. Mutant p53 not only, no longer, functions as a tumor suppressor but can also exert tumor-promoting effects. The basic function of p53 is to respond to cellular stress. We herein review the recent advances in p53 research and focus on apoptosis, cell cycle arrest, and senescence in response to stress. We also review the clinical applications of p53-based therapy for human cancer.