In this review we will consider the integral role that the p53/MDM2 axis plays in the interactions between CDK4/6, ERα, and inhibitors of these molecules, the current preclinical evidence for the efficacy of MDM2 inhibitors in ER+ breast cancer, and discuss the possible outcomes of targeting p53/MDM2 in the CDK4/6i resistance setting. The gene discussed is ESR1; the disease is breast cancer.