The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. 
Wild-type p53 can suppress tumour development by multiple pathways. However, 
mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour 
cell death and rapid tumour progression. The high frequency of TP53 mutation in 
tumours has prompted efforts to restore normal function of mutant p53 and 
thereby trigger tumour cell death and tumour elimination. Small molecules that 
can reactivate missense-mutant p53 protein have been identified by different 
strategies, and two compounds are being tested in clinical trials. Novel 
approaches for targeting TP53 nonsense mutations are also underway. This Review 
discusses recent progress in pharmacological reactivation of mutant p53 and 
highlights problems and promises with these strategies.