This study investigates the in vivo imaging of specialized bone marrow (BM) endothelial microdomains that support tumor engraftment. Using dynamic confocal microscopy, the authors found that the murine BM contains unique regions defined by specialized endothelium expressing E-selectin and SDF-1, which are crucial for the homing of various tumor cell lines. Disruption of SDF-1/CXCR4 interactions inhibits Nalm-6 cell (acute lymphoblastic leukemia) homing to these vessels. Further studies revealed that circulating leukemic cells engraft around these vessels, suggesting that this molecularly distinct vasculature forms a microenvironment for early metastatic tumor spread in the BM. Additionally, purified hematopoietic stem/progenitor cells and lymphocytes also localize to these microdomains, indicating that this vasculature may function in benign states to demarcate specific portals for cell entry into the marrow space. The findings highlight the importance of these specialized vascular structures in regulating the microenvironment and their potential as targets for therapeutic intervention in metastatic disease.This study investigates the in vivo imaging of specialized bone marrow (BM) endothelial microdomains that support tumor engraftment. Using dynamic confocal microscopy, the authors found that the murine BM contains unique regions defined by specialized endothelium expressing E-selectin and SDF-1, which are crucial for the homing of various tumor cell lines. Disruption of SDF-1/CXCR4 interactions inhibits Nalm-6 cell (acute lymphoblastic leukemia) homing to these vessels. Further studies revealed that circulating leukemic cells engraft around these vessels, suggesting that this molecularly distinct vasculature forms a microenvironment for early metastatic tumor spread in the BM. Additionally, purified hematopoietic stem/progenitor cells and lymphocytes also localize to these microdomains, indicating that this vasculature may function in benign states to demarcate specific portals for cell entry into the marrow space. The findings highlight the importance of these specialized vascular structures in regulating the microenvironment and their potential as targets for therapeutic intervention in metastatic disease.