The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 
(INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating 
the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway 
results in increased proliferation, and is frequently observed in many types of 
cancer. Pathway activation can occur through a variety of mechanisms, including 
gene amplification or rearrangement, loss of negative regulators, epigenetic 
alterations, and point mutations in key pathway components. Due to the 
importance of CDK4/6 activity in cancer cells, CDK4/6 inhibitors have emerged as 
promising candidates for cancer treatment. Moreover, combination of a CDK4/6 
inhibitor with other targeted therapies may help overcome acquired or de novo 
treatment resistance. Ongoing studies include combinations of CDK4/6 inhibitors 
with endocrine therapy and phosphatidylinositol 3-kinase (PI3K) pathway 
inhibitors for hormone receptor-positive (HR+) breast cancers, and with 
selective RAF and MEK inhibitors for tumors with alterations in the mitogen 
activated protein kinase (MAPK) pathway such as melanoma. In particular, the 
combination of CDK4/6 inhibitors with endocrine therapy, such as palbociclib's 
recent first-line approval in combination with letrozole, is expected to 
transform the treatment of HR+ breast cancer. Currently, three selective CDK4/6 
inhibitors have been approved or are in late-stage development: palbociclib 
(PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Here we describe 
the current preclinical and clinical data for these novel agents and discuss 
combination strategies with other agents for the treatment of cancer.