External and internal signals regulate the core cell-cycle machinery, including cyclins and CDK inhibitors. While mitogenic signals are known to regulate cyclin D expression, recent work has shown that endogenous DNA damage leads to the upregulation of p21. Additionally, extrinsic and intrinsic growth signals contribute to cell-cycle decisions. We propose a model in which the cell cycle decisions rely on the combined effects of pro-and anti-growth signals and their integration by their combined effects on the expression of CDKs, cyclins, and CDK inhibitors. This model is consistent with an ultrasensitive activation of CDKs.