While endocrine monotherapy has been a mainstay in treating metastatic ER+ breast cancer for decades, multiple pivotal clinical trials in recent years have demonstrated that the addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to an endocrine agent, such as an aromatase inhibitor or a SERD such as fulvestrant, significantly increases progression-free survival (PFS) when compared to the endocrine agent alone [5, 12–17]. The gene discussed is CDK4; the disease is breast carcinoma.