Inactivation of cyclin-dependent kinases (Cdks) and/or cyclins in mice has changed our view of cell cycle regulation. In general, cells are far more resistant to the loss of Cdks than originally anticipated, suggesting widespread compensation among the Cdks. Early embryonic cells are, so far, not sensitive to the lack of multiple Cdks or cyclins. In contrast, differentiated cells are more dependent on Cdk/cyclin complexes and the functional redundancy is more limited. Our challenge is to better understand these cell-type specific differences in cell cycle regulation that can be used to design efficient cancer therapy. Indeed, tumor cells seem to respond to inhibition of Cdk activities, however, with different outcome depending on the tumor cell type. Tumor cells share some proliferation features with stem cells, but appear more sensitive to loss of Cdk activity, somewhat resembling differentiated cells. We summarize the current knowledge of cell cycle regulation in different cell types and highlight their sensitivity to the lack of Cdk activities.