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Specific tissue microenvironments, or niches, are critical for homing and maintenance of both stem cells and tumor cells in vivo. Little is known, however, about the molecular interactions between individual cells within these microenvironments. Recent studies that describe a newly identified hematopoietic stem and tumor cell vascular niche in the bone marrow (BM) suggest a critical role for vascular endothelial cell signaling and raise the possibility that bidirectional interactions of these cells with the vasculature regulate the niche dynamically. The mechanisms that govern hematopoietic stem cell (HSC)/tumor cell cross-talk with endothelial cells provide a promising new direction for future studies. Here we review recent advances that open new avenues of study in this field.