Brain tumors remain one of the most difficult tumors to treat and, depending on the diagnosis, have a poor prognosis. Of brain tumors, glioblastoma (GBM) is the most common malignant glioma and has a dismal prognosis, with only about 5% of patients alive five years after diagnosis. While advances in targeted therapies and immunotherapies are rapidly improving outcomes in a variety of other cancers, the standard of care for GBM has largely remained unaltered since 2005. There are many well-studied challenges that are either unique to brain tumors (i.e., blood-brain barrier and immunosuppressive environment) or amplified within GBM (i.e., tumor heterogeneity at the cellular and molecular levels, plasticity, and cancer stem cells) that make this disease particularly difficult to treat. While we touch on all these concepts, the focus of this review is to discuss the immense inter- and intra-tumoral heterogeneity and advances in our understanding of tumor cell plasticity and epigenetics in GBM. With each improvement in technology, our understanding of the complexity of tumoral heterogeneity and plasticity improves and we gain more clarity on the causes underlying previous therapeutic failures. However, these advances are unlocking new therapeutic opportunities that scientists and physicians are currently exploiting and have the potential for new breakthroughs.