Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal types of cancer in children. In recent years, it has become evident that these tumors are driven by epigenetic events, mainly mutations involving genes encoding Histone 3, setting them apart from their adult counterparts. These tumors are exceptionally resistant to chemotherapy and respond only temporarily to radiotherapy. Moreover, their delicate location and diffuse growth pattern make complete surgical resection impossible. In many other forms of cancer, chemo- and radioresistance, in combination with a diffuse, invasive phenotype, are associated with a transcriptional program termed the epithelial-to-mesenchymal transition (EMT). Activation of this program allows cancer cells to survive individually, invade surrounding tissues and metastasize. It also enables them to survive exposure to cytotoxic therapy, including chemotherapeutic drugs and radiation. We here suggest that EMT plays an important, yet poorly understood role in the biology and therapy resistance of pHGG and DIPG. This review summarizes the current knowledge on the major signal transduction pathways and transcription factors involved in the epithelial-to-mesenchymal transition in cancer in general and in pediatric HGG and DIPG in particular. Despite the fact that the mesenchymal transition has not yet been specifically studied in pHGG and DIPG, activation of pathways and high levels of transcription factors involved in EMT have been described. We conclude that the mesenchymal transition is likely to be an important element of the biology of pHGG and DIPG and warrants further investigation for the development of novel therapeutics.