We’ve known since the early 2000s that too much TMZ is bad for the brain. Then, in 2009, we learned that ex vivo cultured glioblastoma cells treated with the chemotherapy temozolomide (TMZ) developed robust MGMT expression conferring TMZ-resistance--an interesting, if not practice changing, observation. While we’re waiting on the final results of the CATNON and CODEL trials evaluating the role of upfront TMZ in low grade gliomas, read up on the newest TMZ genomic findings. A subset of recurrent gliomas showed evidence of TMZ-induced hypermutation, though it’s unclear if this drives malignant progression. TBL: We now have in vivo evidence of TMZ-induced radically altered recurrent glioma genomes, opening the door to a whole host a novel therapeutics for this population...and to novel concerns about undesired biologic consequences of TMZ treatment.