The success of anti-vascular endothelial growth factor (VEGF) therapy has mainly been attributed to its effects on tumor angiogenesis. Beck et al. now show that VEGF signaling is also important for the maintenance of tumor stem cells. Working with a mouse model of squamous skin tumors, the authors show that tumor stem cells are localized close to endothelial cells and that blocking VEGF-receptor 2 not only reduced blood vessel density in the tumor but also decreased the number of cancer stem cells. In addition to promoting the formation of a cancer stem cell niche by regulating angiogenesis, VEGF also has a direct effect on the cancer stem cells, as selective deletion of the VEGF co-receptor neuropilin-1, which is normally expressed in cancer stem cells, also caused an inhibition of cancer stem cell self-renewal and differentiation. The involvement of a VEGF signaling pathway in cancer stem cell biology might provide new therapeutic avenues in the future. (Nature 478, 399–403, 2011)