Pediatric glioblastoma harbors an unexpected degree of intratumoral genetic heterogeneity. The coexistence of genetic subclones is here represented as branches of a tree with cells/leaves of different colors. Some of these subclones are more ancestral than others, as represented by their earlier branching points. Subclonal compartments are fueled by slow-cycling cancer stem cells, which are represented as the roots of the tree. Four cancer stem cells (pink, orange, blue, and yellow) each generated branches (or subclones) of the same color. However, one cancer stem cell (black) is mostly dormant and will produce its progeny at relapse. The cancer stem cell architecture of pediatric glioblastoma may explain why the genetic makeup of diagnostic and relapse samples are widely different. For details, see article by Hoffman and colleagues on page 2111.