E2F1， E2F2， and E2F3A， the three activators of the E2F family of transcription factors， are key regulators of the G1/S transition， promoting transcription of hundreds of genes critical for cell-cycle progression. We found that during late S and in G2， the degradation of all three activator E2Fs is controlled by cyclin?F， the substrate receptor of 1 of 69 human SCF ubiquitin ligase complexes. E2F1， E2F2， and E2F3A interact with the cyclin box of cyclin F via their conserved N-terminal cyclin binding motifs. In the short term， E2F mutants unable to bind cyclin F remain stable throughout the cell cycle， induce unscheduled transcription in G2 and mitosis， and promote faster entry into the next S phase. However， in the long term， they impair cell fitness. We propose that by restricting E2F activity to the S phase， cyclin?F controls one of the main and most critical transcriptional engines of the cell cycle.