Cell–cell and cell–extracellular matrix interactions between hematopoietic stem cells (HSCs) and their niches are critical for the maintenance of stem cell properties. Here, it is demonstrated that a cell adhesion molecule, N‐cadherin, is expressed in hematopoietic stem/progenitor cells (HSPCs) and plays a critical role in the regulation of HSPC engraftment. Furthermore, overexpression of N‐cadherin in HSCs promoted quiescence and preserved HSC activity during serial bone marrow (BM) transplantation (BMT). Inhibition of N‐cadherin by the transduction of N‐cadherin short hairpin (sh) RNA (shN‐cad) reduced the lodgment of donor HSCs to the endosteal surface, resulting in a significant reduction in long‐term engraftment. shN‐cad‐transduced cells were maintained in the spleen for six months after BMT, indicating that N‐cadherin expression in HSCs is specifically required in the BM. These findings suggest that N‐cadherin‐mediated cell adhesion is functionally essential for the regulation of HSPC activities in the BM niche.