The transcription factor p53 is known as the guardian of the genome for its powerful anti-tumour capacity. However, mutations of p53 that undermine their protein structure, resulting in loss of tumour suppressor function and gain of oncogenic function, have been implicated in more than half of human cancers. The crucial role of mutant forms of p53 in cancer makes it an attractive therapeutic target. A large number of candidates, including low MW compounds, peptides, and nucleic acids, have been identified or designed to rescue p53 mutants and reactivate their anti-tumour capacity through a variety of mechanisms. In this review, we summarize the progress made in the reactivation of mutant forms of p53, focusing on the pharmacological mechanisms of the reactivators of p53 mutants.