Treatment of metastatic breast cancer (MBC) that is resistant to endocrine 
therapy presents a significant clinical challenge. The well-known role of cell 
cycle dysregulation in these patients is partly mediated by cyclin-dependent 
kinase (CDK) activity. Specific cyclin and CDK complexes regulate cell cycle 
progression by managing the transition through the cell cycle, and inhibition of 
CDKs represents an important target for novel agents. First-generation CDK 
inhibitors (e.g., flavopiridol) were relatively nonselective and had an 
unacceptable toxicity profile in early trials. Second-generation CDK inhibitors 
were designed to target the CDK4 and CDK6 (CDK4/6) pathway and have shown 
promising clinical activity with an acceptable toxicity profile in patients with 
MBC. Palbociclib is a first-in-class CDK4/6 inhibitor that was granted 
accelerated U.S. Food and Drug Administration approval in combination with 
letrozole for the treatment of MBC in the first-line setting (February 2015) as 
well as in combination with fulvestrant for MBC that had progressed on previous 
endocrine therapy (February 2016). Other CDK4/6 inhibitors, including ribociclib 
and abemaciclib, are under investigation as monotherapy and in combination with 
endocrine or anti-human epidermal growth receptor 2 therapy for the treatment of 
MBC. Ongoing clinical trials should provide additional information to guide the 
appropriate use of these agents and identify patient populations that could 
derive the most benefit.