There is now compelling evidence that brain tumors harbor a small population of cells characterized by their ability to undergo self-renewal and initiate tumors, termed cancer stem cells (CSCs). The development of therapeutic strategies targeted towards CSC signaling may improve the treatment of brain tumors such as malignant gliomas and medulloblastomas. Here we review the role of cancer stem cells in glioma and medulloblastoma and some of the signaling mechanisms involved in brain tumor stem cell (BTSC) biology, and discuss how these signaling pathways may represent new stem cell targets for the treatment of brain tumors. In addition, we provide illustrative immunohistochemical data on the presence of BTSCs in human gliomas and medulloblastomas, and show preliminary findings suggesting the involvement of a GPCR, the gastrin-releasing peptide receptor (GRPR), in the expansion of BTSCs in vitro.