Despite the wide experimental preclinical work on cyclin-D1/CDK4 and CDK6 inhibitors in several neoplasms, these agents have been mostly clinically tested only for advanced and metastatic malignancies and just recently have been approved as a standard first-line strategy in HR-positive, HER2 negative breast cancer, in various combinations with AIs, SERMs, or SERDs. This evidence concerns the gene CDK6 and breast cancer.