When preadipocytes reenter the cell cycle, PPARγ expression is induced, coincident with an increase in DNA synthesis, suggesting the involvement of the E2F family of cell cycle regulators. We show here that E2F1 induces PPARγ transcription during clonal expansion, whereas E2F4 represses PPARγ expression during terminal adipocyte differentiation. Using a combination of in vivo experiments with knockout and chimeric animals and in vitro experiments, we demonstrate that the absence of E2F1 impairs, whereas depletion of E2F4 stimulates, adipogenesis. E2Fs hence represent the link between proliferative signaling pathways, triggering clonal expansion, and terminal adipocyte differentiation through regulation of PPARγ expression. This underscores the complex role of the E2F protein family in the control of both cell proliferation and differentiation.