After a decade of extensive work on gene knockout mouse models of cell-cycle regulators, the classical model of cell-cycle regulation was seriously challenged. Several unexpected compensatory mechanisms were uncovered among cyclins and Cdks in these studies. The most astonishing observation is that Cdk2 is dispensable for the regulation of the mitotic cell cycle with both Cdk4 and Cdk1 covering for Cdk2's functions. Similar to yeast, it was recently discovered that Cdk1 alone can drive the mammalian cell cycle, indicating that the regulation of the mammalian cell cycle is highly conserved. Nevertheless, cell–cycle-independent functions of Cdks and cyclins such as in DNA damage repair are still under investigation. Here we review the compensatory mechanisms among major cyclins and Cdks in mammalian cell-cycle regulation.