Cancer research has rediscovered the complexity of nervous system cancers through the incorporation of cellular heterogeneity into tumor models with cellular subsets displaying stem cell characteristics. The cancer stem cell hypothesis posits that tumor cells are organized in a hierarchy with cancer stem cells at the apex and functionally defined by the ability to self renew and propagate tumors similar to the parental tumors from which they are derived. The clinical relevance of cancer stem cells has been supported by cancer stem cell resistance to cytotoxic therapies and promotion of tumor angiogenesis. Cancer stem cells reside in specific functional niches in perivascular and hypoxic niches that may offer the ability to disrupt tumor maintenance and therapeutic resistance through targeting the niche. The cancer stem cell phenotype is regulated by both cell intrinsic and microenvironmental influences that may further increase the complexity of tumor modeling. The study of cellular heterogeneity and cancer stem cells has already yielded novel molecular targets and pathways that are amenable to therapeutic targeting, perhaps permitting attenuation of tumor resistance. The conventional pyramidal unidirectional differentiation cascade with cancer stem cells at the apex has been called into question by studies demonstrating plasticity of the cancer stem cell phenotype, thus suggesting that targeting only cancer stem cells will likely fail to cure patients and require simultaneous targeting of cancer stem cells and the bulk tumor. The field of cancer stem cell biology holds promise for the development of novel patient therapies.