Maintenance of a relatively quiescent cell cycle state is a distinct characteristic of adult hematopoietic stem cells (HSCs) residing in the bone marrow (BM) microenvironment. This property is considered critical for HSCs to fulfill long term self-renewal and multi-lineage differentiation potential throughout mammalian life span. To date, the mechanisms regulating the cell cycle state and the retention of HSCs in the BM microenvironment remain unclear. Cdc42, a small GTPase of the Rho family known to control various cellular functions including adhesion, migration, transcription, and growth, is shown recently in a conditional gene-targeted mouse model to coordinate HSC quiescence maintenance and BM niche residency. The study also highlights a cell-type specific role of Cdc42 in cell cycle regulation.