Mouse models of malignant glioma that accurately recapitulate the genetic and phenotypic heterogeneity are essential for advancing brain tumor therapeutics. We have developed a novel model using the Sleeping Beauty transposable element to achieve chromosomal integration of human oncogenes into endogenous brain cells of any mouse strain. The phenotype of these genetically engineered brain tumors is influenced by the combination of oncogenes delivered, but many of the pathological features of malignant human glioma are present in the majority of cases. At least five different genes can be cotransfected simultaneously, including reporters that allow measurement of tumor progression. The flexibility of this model enabled studies on the role of the microenvironment in brain tumor development. The data presented here demonstrate that glioma cells make an abundance of CD44 and HA starting early in tumor development and continue to make both receptor and ligand as gliomas progress to highly invasive disease. We show that CD44-/- tumors progressed significantly slower than CD44+/+ tumors, but that expression of full length CD44 within tumors restores the CD44-/- tumor progression. In addition, we show that CD44 loss of function caused severe impairment in single cell motility. The data presented here suggest that HA-engaged CD44 mediates tumor progression by facilitating glioma cell invasion. These studies highlight the therapeutic potential for targeting the infiltrative glioma population through antagonists of the HA-CD44 complex.