High grade glioma remains the most intractable childhood tumor of the central nervous system. The molecular genetics of childhood high grade glioma remain largely unknown in comparison to that of their adult counterparts. In an era of molecularly targeted therapies, this dearth of knowledge will present particular challenges to those who must design and implement the next generation of therapeutic trials with these new agents. In this review, we discuss the current understanding of the molecular genetics of childhood high grade glioma and compare/contrast it to that of the adult tumors bearing the same classification for the purpose of beginning to identify the most promising therapeutic targets.