Emerging evidence from numerous laboratories supports the notion that brain tumors arise from cells with stem cell/neuroglial progenitor cell properties ("cancer stem cells"). Two recent studies suggest that histologically similar tumors from different brain regions are molecularly distinct because they arise from distinct populations of site-restricted progenitor cells. These new findings imply an interaction between the cell of origin, the tumor microenvironment, and specific cancer-causing genetic changes in the evolution of central nervous system tumors.