The mammalian cell cycle machinery contains multiple cyclin-dependent kinases (Cdks) that are thought to have specific functions. For example, Cdk1 is proposed to be essential for mitotic entry and exit, whereas Cdk2 drives cells through the G1-S phase transition. Yet, surprisingly, Cdk1 can partially compensate for Cdk2 loss, even though Cdk2 remains essential for meiosis. Now,on p. 3389, Ande Satyanarayana and colleagues demonstrate that Cdk2 cannot compensate for the lack of Cdk1 during mouse embryogenesis, even when expressed from a Cdk1 promoter. They report that Cdk1 deletion leads to early embryonic death, as does substituting Cdk2 for both copies of Cdk1 to eliminate differences in the timing of expression. Conversely, Cdk2-/- mice in which one Cdk1 copy is replaced by Cdk2 are sterile, showing that Cdk1-driven Cdk2 expression cannot rescue the Cdk2-/- meiotic defect. The mitotic function of Cdk2, however, is not affected. These results confirm that Cdk1 is essential for mammalian development and highlight the functional differences amongst mammalian Cdks.