Hematopoietic stem cells (HSCs) are characterized by pluripotentiality and self-renewal ability. To maintain a supply of mature blood cells and to avoid HSC exhaustion during the life span of an organism, most HSCs remain quiescent, with only a limited number entering the cell cycle.

The molecular mechanisms by which quiescence is maintained in HSCs are addressed, with recent genetic studies having provided important insight into the relation between the cell cycle activity and stemness of HSCs.

The cell cycle is tightly regulated in HSCs by complex factors. Key regulators of the cell cycle in other cell types—including cyclins, cyclin-dependent kinases (CDKs), the retinoblastoma protein family, the transcription factor E2F, and CDK inhibitors—also contribute to such regulation in HSCs. Most, but not all, of these regulators are necessary for maintenance of HSCs, with abnormal activation or suppression of the cell cycle resulting in HSC exhaustion. The cell cycle in HSCs is also regulated by external factors such as cytokines produced by niche cells as well as by the ubiquitin–proteasome pathway.

Studies of the cell cycle in HSCs may shed light on the pathogenesis of hematopoietic disorders, serve as a basis for the development of new therapeutic strategies for such disorders, prove useful for the expansion of HSCs in vitro as a possible replacement for blood transfusion, and provide insight into stem cell biology in general. This article is part of a Special Issue entitled Biochemistry of Stem Cells.