Leukemia arises from leukemic stem cells, which reside within the bone marrow occupying two different stem cells niches: the endosteal and the vascular niche. The maintenance of leukemic stem cells requires complex regulation mediated by many intrinsic and extrinsic signals provided by their niche cells. The interaction of leukemic and endothelial cells can occur either via direct contact through cell adhesion molecules such as selectins or integrins or signals can be transmitted by chemokines or cytokines of which stromal cell-derived factor 1 represents the most studied. Experimental studies provide evidence that targeting molecules involved in the interaction of leukemic and endothelial cells might represent a promising therapeutic target. Indeed, first clinical trials considering this concept are currently under investigation.