The p53 family proteins are among the most appealing targets for cancer therapy. A deeper understanding of the complex interplay that these proteins establish with murine double minute (MDM)2, MDMX, and mutant p53 could reveal new exciting therapeutic opportunities in cancer treatment. Here, we summarize the most relevant advances in the biology of p53 family protein-protein interactions (PPIs), and the latest pharmacological developments achieved from targeting these interactions. We also highlight the remarkable contributions of yeast-based assays to this research. Collectively, we emphasize promising strategies, based on the inhibition of p53 family PPIs, which have expedited anticancer drug development.