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Abnormal activation of the cyclin-dependent kinases(CDKs),which result in aberrant cell proliferation,is one of the inherent characteristics of tumor.Thus targeting the activity of CDKs represents a promising tumor therapeutic strategy.Currently,the specific inhibitors that target CDK4 and CDK6 have been approved for the treatment of estrogen receptor positive,human epidermal growth factor receptor 2 negative(ER+HER2-)breast cancer in combination with endocrine therapy;other combination strategies are being tested in a number of clinical trials.However,the acquired resistance to CDK4/6 inhibitors has emerged.As the cell cycle is orchestrated by a series of biological events,the alterations of other molecular events that regulate the cell cycle progression may be involved in intrinsic resistance to CDK4/6 inhibitors.In this review we mainly discuss the mechanisms underlying intrinsic resistance and acquired resistance to CDK4/6 inhibitors as well as combination strategies with other signal pathway inhibitors being tested in clinical and pre-clinical studies,to extend the use of CDK4/6 inhibitors in tumor treatment.