Cyclin A, the first cyclin ever cloned, is thought to be an essential component of the cell cycle engine. Mammalian cells encode two A-type cyclins, testis-specific cyclin A1 and ubiquitously expressed cyclin A2. Here we tested the requirement for cyclin A function using conditional knockout mice lacking both A-type cyclins. We found that acute ablation of cyclin A in fibroblasts did not affect cell proliferation, but led to prolonged expression of cyclin E across the cell cycle. However, combined ablation of all A- and E-type cyclins extinguished cell division. Hence, in fibroblasts cyclins A and E play redundant roles in cell proliferation. In contrast, ablation of cyclin A in bone marrow obliterated hematopoiesis. We found that cyclin A function was essential for proliferation of hematopoietic and embryonal stem cells. In these compartments cyclin A-Cdk complexes are expressed at particularly high levels, which may render stem cells dependent on cyclin A.