p53 is one of the most well-studied tumor suppressors. It is mutated or deleted in half of all cancers. In the other half carrying wild type p53, the p53 signaling pathway is disrupted by abnormalities of other components in the pathway. Due to its paramount role in tumor suppression, p53 has attracted great interest in drug development as any clinically successful therapeutic agent to target the p53 pathway will save millions of lives. However, designing therapeutics targeting the pathway has been extremely challenging, despite more than forty years of research. This review will summarize past and current efforts of developing p53-based gene therapy and targeted therapies for cancer treatment. In addition, the current efforts of exploiting the immunogenicity of p53 protein for cancer immunotherapy will be reviewed. Challenges and future directions for targeting the p53 pathway will be discussed.