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. Using a wide variety of methodologies – including genetically engineered mouse models, cell-based assays, patient-derived xenografts, and analysis of clinical specimens - we have uncovered novel mechanisms of activity for CDK4/6 inhibitors in breast cancer. In my talk, I will present the results of our recent studies, discuss the clinical trials that have arisen from our laboratory data, and suggest future directions for research in this field.