Moving forward, key unanswered questions must be addressed with the goals of (1) enhancing the efficacy of CDK4/6 inhibitors in HR-positive breast cancer through identification of novel therapeutic combinations; (2) interrogating the plasticity of the cell cycle machinery in breast cancer as a means to understanding acquired resistance; and (3) extending the use of these agents to other breast cancer subtypes. This evidence concerns the gene CDK4 and breast cancer.