Although the molecular changes that characterize gliomas have been studied, the pathogenesis of tumor development remains unclear. p21 contributes to gliomagenesis by stabilizing cyclin D1–cdk4 kinase complexes, suggesting that cyclin D1 and cdk4 may also be required for glial tumor development. In this study, we used a mouse model to attempt to confirm this hypothesis, finding that cyclin D1 and cdk4 played active roles in not only the tumor but also the tumor microenvironment. Loss of cdk4 blocked tumor development, but loss of cyclin D1 did not prevent gliomas from developing. Instead, loss of cyclin D1 impeded progression to higher stages of malignancy. Enforcing expression of cyclin D1 was insufficient to correct the progression defect observed in cyclin D1–deficient animals. In contrast, restoration of cdk4 in the cdk4-deficient animals restored cell proliferation and tumor formation, although at lower tumor grades. Notably, the failure of tumors in the cyclin D1- and cdk4-deficient animals to progress to higher grades was correlated with a failure to fully activate microglia in the tumor microenvironment. Moreover, when platelet-derived growth factor–transformed glial cells were engrafted orthotopically into the mice, the tumors that formed progressed to high grades in wild-type mice but not cyclin D1–deficient animals. Together, our findings establish that the cyclin D1–cdk4 axis is not only critical in glial tumor cells but also in stromal-derived cells in the surrounding tumor microenvironment that are vital to sustain tumor outgrowth. Cancer Res; 71(19); 6174–83. ©2011 AACR.