Abstract: Cyclin-dependent kinases (CDKs) inhibitors have been approved in the combination with hormone-based therapy for advanced breast cancer. In addition to endocrine therapy, the combinations of CDK4/6 inhibitors with epidermal growth factor receptor (EGFR) inhibitors, phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, chemotherapy, immune therapy, molecular targeted agents and the other therapeutics could overcome its resistance and improve clinical benefits. CDK4/6 inhibitors-based combinational therapeutics provides a promising window for human cancer treatment.