Glioblastoma (GBM) is a rare tumor and one of the most challenging malignancies to treat in all of oncology. Although advances have been made in the treatment of GBM, encouraging outcomes typically are not observed; patients diagnosed with these tumors generally have a dismal prognosis and poor quality of life as the disease progresses. This review summarizes the clinical presentation of GBM, diagnostic methods, evidentiary basis for the current standards of care, and investigational approaches to treat or manage GBM. Because the track record for developing effective therapies for GBM has been dismal, we also review the challenges to successful therapeutic and biomarker development.