: Malignant gliomas are the most common and aggressive primary brain tumor with current available therapies increasing median survival to a modest 20 months. Multiple preclinical research efforts aim to further this improvement through advances in therapeutic options for these patients.: The unique obstacles that must be managed in developing and delivering safe and efficacious therapeutics into the central nervous system are reviewed. We describe the successes and challenges in local drug delivery in the field of neuro-oncology and explore convection enhanced delivery and high frequency ultrasound as tools for safe and effective delivery. Drug delivery systems are described in addition to combination therapies that are being tested both preclinically, as well as ones currently in clinical trials. The field of immunotherapy is also discussed along with specific considerations as it relates to the brain’s microenvironment.: While there have been incremental advances in brain cancer therapeutics over the last few years, novel therapeutics are expanding with multiple opportunities in neuro-oncology. Overcoming the brain’s unique challenges might allow for breakthroughs and discoveries in the future.