Dysregulation of the cyclin D-cyclin-dependent kinase (CDK) 
4/6-INK4-retinoblastoma (Rb) pathway is an important contributor to endocrine 
therapy resistance. Recent clinical development of selective inhibitors of CDK4 
and CDK6 kinases has led to renewed interest in cell cycle regulators, following 
experience with relatively non-selective pan-CDK inhibitors that often resulted 
in limited activity and poor safety profiles in the clinic. The highly selective 
oral CDK 4/6 inhibitors palbociclib (PD0332991), ribociclib (LEE011), and 
abemaciclib (LY2835219) are able to inhibit the proliferation of Rb-positive 
tumor cells and have demonstrated dose-dependent growth inhibition in ER+ breast 
cancer models. In metastatic breast cancer, all three agents are being explored 
in combination with endocrine therapy in Phase III studies. Results so far 
indicated promising efficacy and manageable safety profiles, and led to the FDA 
approval of palbociclib. Phase II-III studies of these agents, in combination 
with endocrine therapy, are also underway in early breast cancer in the 
neoadjuvant and adjuvant settings. Selective CDK 4/6 inhibitors are also being 
investigated with other targeted agents or chemotherapy in the advanced setting. 
This article reviews the rationale for targeting cyclin D-CDK 4/6 in hormone 
receptor-positive (HR+) breast cancer, provides an overview of the available 
preclinical and clinical data with CDK 4/6 inhibitors in breast cancer to date, 
and summarizes the main features of ongoing clinical trials of these new agents 
in breast cancer. Future trials evaluating further combination strategies with 
CDK 4/6 backbone and translational studies refining predictive biomarkers are 
needed to help personalize the optimal treatment regimen for individual patients 
with ER+ breast cancer.