All eukaryotic cells possess similar mechanisms to regulate the progression of the cell cycle. However, higher eukaryotes have evolved to respond to a large array of positive and negative signals with an intracellular or extracellular origin. These signals are eventually integrated by a conserved protein engine consisting of holoenzymes with kinase activity, which trigger crucial transitions during the cell cycle. In this review, the mechanisms by which the mammalian cell cycle engine integrates intracellular and extracellular signals of different nature are discussed.