The classification of brain tumors has evolved from a morphological and histological basis to one that is now in keeping with the advances of modern technology consisting of novel molecular subgroups rooted in clinical outcome and risk stratification. In this chapter, we discuss recent and emerging genomic findings that may be of clinical utility in the foreseeable future for adult and pediatric glioblastoma, pediatric medulloblastoma, ependymoma, and diffuse intrinsic pontine glioma. Moreover, limitations in the current molecular classification of these tumors are discussed with the brain tumor-initiating cell and cancer stem cell model as frameworks for future research efforts in identifying novel genomic alterations for better discerning the intratumoral heterogeneous landscape of these solid tumors as an avenue for developing tumor subgroup-specific targeted therapy.