Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. At diagnosis, low grade brain tumors have similar histology and driver mutations, but following surgical resection their clinical behavior is highly variable. Infiltrating tumor cells comprising the residual disease may remain indolent for more than a decade after the surgical resection, or may rapidly transform into an aggressive rapidly growing malignant tumor. Adjuvant chemotherapies such as temozolomide (TMZ) are frequently used, especially in cases with subtotal surgical resections or when deferring the use of radiation therapy is preferable. We used genome and epigenome sequencing technologies to infer patterns of intratumoral heterogeneity and tumor evolution over time. In this presentation I will discuss new insight into diverging genetic pathways arising from initially similar tumors, and the profound influence of chemotherapy in shaping tumor aggressiveness.