Previous studies have demonstrated that mice lacking Cyclin D1 were refractory to mammary tumor development induced by the c-neu/erbB-2 oncogene, the rodent ortholog of the HER-2 receptor frequently overexpressed in human breast carcinomas. Two new studies in this issue of Cancer Cell provide additional evidence on this issue. Knockin mice expressing a mutant form of Cyclin D1 that binds to Cdk4/6 but cannot activate their catalytic activity are resistant to c-neu/erbB-2 tumorigenesis in spite of undergoing normal epithelial cell expansion during pregnancy. Moreover, knockdown of Cdk4 in mammary tumor cells abrogates tumor formation. These observations provide new compelling evidence that inhibition of Cyclin D1-Cdk4/6 kinases might be beneficial for cancer therapy.