Glioblastoma (GBM) is a highly aggressive and prevalent adult brain tumor. Despite an intensive standard of care consisting of surgical resection followed by radiation therapy and chemotherapy with temozolomide, patients invariably succumb to the recurrent tumor and face an overall survival of less than 15 months. Recurrent GBM often differs greatly from the primary counterparts and show greater resistance to genotoxic therapies. Despite these differences and implications this treatment resistance has, recurrent GBM remains relatively understudied due to the paucity of samples and a previous lack of interest in the field. In this chapter, we describe an in vivo xenograft model recapitulating the standard of care with radiation therapy and temozolomide, and the subsequent development of recurrent GBM.