Proteoglycans are key molecules in signaling, both during brain development and in malignant brain tumor formation, where cancer cells mimic, or co-opt, normal developmental programs. This chapter focuses on the role of heparan sulfate proteoglycans (HSPGs) in these processes. HSPGs are composed of a core protein with attached, heavily sulfated, polysaccharide side chains, and they are ubiquitously present on cell surfaces and in the extracellular space where they serve both as structural components and regulators of a multitude of cellular activities. HSPGs are critically involved in mammalian development, and perturbations of pathways regulated by HSPGs play major roles in human diseases. Neural stem cell programs sustain populations of stem cells that initially give rise to neural progenitors with high proliferative capacity that eventually differentiate to mature cells of the nervous system. HSPGs act as coreceptors for a wide variety of signaling pathways during these processes. Accumulated mutations in neural stem cells can cause failure to perform terminal differentiation or the inability to restrict progenitor proliferation and lead to brain tumor development. The same signaling mechanisms that promote self-renewal of neural stem cells thus also support cancer stem cells, and HSPGs are integral facilitators of brain tumor development and progression.