The scientific community has been studying the D-type cyclins and their related cyclin-dependent kinases (CDK4 and CDK6) for decades. These efforts have left us with a plethora of information regarding the functions of these molecules within cancer cells. It is only recently, however, that selective pharmacologic inhibitors of CDK4/6 have become available. In this presentation, I will review the biology of the CDK4/6 pathway, the results of recent trials of CDK4/6 inhibition in breast cancer, and future approaches that might enhance the therapeutic effect of these agents.