In this review article, I comprehensively review the chronological identification of mortalin-p53 interaction, cover salient achievements in the identification and development of the compounds that have been reported to possess the potentiality to abrogate such an interaction as possible cancer therapeutic strategy, and finally provide insights into the reasons why the disruption of this notorious protein-protein interaction, although a druggable target, has not been yet translated into clinics. Here, HSPA9 is linked to cancer.