The aim of this review, based on the publications referenced in PubMed since 2002 and using the key words PRIMA-1 or APR-246, is (1) to question, 15 years after their discovery, the initial published properties of PRIMA-1 and APR-246 (cancer growth inhibition and mutant-p53 reactivation), (2) to present the new hypothetical mechanisms of action of these molecules, and (3) to list and comment the therapeutic associations already tested and ongoing, in order to prepare the future clinical combination of p53 restoration and targeted therapies. This evidence concerns the gene TP53 and cancer.