Tumor-initiating cells (TICs) with stem-like cell properties initiate and sustain progressive growth, resulting in a heterogeneous tumor mass. The survival and growth of tumors rely on the development of a vasculature to provide nutrients and oxygen. Crosstalk between TICs and vascularization may be one of the central players in the initiation, long-term maintenance, and progression of tumors. This review surveys current evidence concerning the crosstalk that occurs in tumor/stromal interactions, including genetic change, vascular niche, hypoxia, and dormancy of tumors. A better understanding of this crosstalk might help provide the basis for developing more effective therapeutic drug targets. Pediatr Blood Cancer 2011;56:335–340. © 2010 Wiley-Liss, Inc.