The cancer stem cell paradigm is the idea that subpopulations of cancer cells exist within a tumor that are capable of self-renewal, multipotency, proliferation, and tumor maintenance. This subpopulation of cells is believed to be responsible for tumor cell treatment resistance and tumor recurrence. In neuroblastoma, the phenotypic characteristics identifying cancer stem cells include expression of certain cell surface markers, expression of certain cytoplasmic and nuclear proteins, efflux of Hoechst 33,342 dye, and the ability to grow as spheres in culture. These cells reside in specialized microenvironments which are composed of non-tumor host cells, immune cells, tumor stromal cells, the extracellular matrix, and cell adhesion molecules. The identification of neuroblastoma cancer stem cell populations and the contribution of the various elements of the tumor microenvironment that support these cells is discussed in this chapter.