Diffuse midline glioma (DMG) is the leading cause of brain tumor-related deaths in children. DMG typically presents with variable neurologic symptoms between ages 3 and 10. Currently, radiation remains the standard therapy for DMG to halt progression and reduce tumor bulk to minimize symptoms. However, tumors recur in almost 100% of patients and thus, DMG is still considered an incurable cancer with a median survival of 9-12 months. Surgery is generally contraindicated due to the delicate organization of the brainstem, where DMG is located. Despite extensive research efforts, no chemotherapeutic agents, immune therapies, or molecularly targeted therapies have been approved to provide survival benefit. Furthermore, the efficacy of therapies is limited by poor blood-brain barrier penetration and inherent resistance mechanisms of the tumor. However, novel drug delivery approaches, along with recent advances in molecularly targeted therapies and immunotherapies, have advanced to clinical trials and may provide viable future treatment options for DMG patients. This review seeks to evaluate current therapeutics at the preclinical stage and those that have advanced to clinical trials and to discuss the challenges of drug delivery and inherent resistance to these therapies.