The brain is a complicated organ with complexity derived from cellular and microenvironmental interactions. Similarly, brain tumor cells actively modify and are regulated by their microenvironment. Brain tumors are highly heterogeneous and frequently show a cellular hierarchy with self-renewing tumorigenic brain tumor stem cells (BTSCs) at the apex. Although BTSCs are distinct from neural stem cells, they share characteristics, including bidirectional interplay with supportive vasculature critical for maintenance of undifferentiated states and survival. BTSCs stimulate angiogenesis through growth factor secretion and are enriched in perivascular niches. Microenvironmental conditions, including hypoxia, drive expression of stem cell genes and proangiogenic factors, further linking cellular hierarchy regulation and instructive stromal elements. BTSCs may also directly contribute to tumor vasculature through plasticity toward an endothelial lineage. Interrogating the codependence of BTSCs and the perivascular niche may directly inform clinical approaches for brain tumor therapy through targeting of highly angiogenic and tumorigenic cellular subsets. © 2011 Nature America, Inc. All rights reserved.