High-grade gliomas, in particularly diffuse midline glioma, H3K27-altered in children and glioblastoma in adults, are the most lethal brain tumour with a dismal prognosis. Developments in modern medicine are constantly being applied in the search for a cure, although finding the right strategy remains elusive. Circumventing the blood-brain barrier is one of the biggest challenges when it comes to treating brain tumours. The cat and mouse game of finding the Trojan horse to traverse this barrier and deliver therapeutics to the brain has been a long and hard-fought struggle. Research is ongoing to find new and feasible ways to reach specific targets in the brain, with a special focus on inoperable or recurring brain tumours. Many options and combinations of options have been tested to date and continue to be so in the search to find the most effective and least toxic treatment paradigm. Although improvements are often small and slow, some of these strategies have already shown promise, shining a light of hope that finding the cure is feasible. In this review, we discuss recent findings that elucidate promising but atypical strategies for targeting gliomas and the implications that this work has on developing new treatment regimens.