Purpose Diffuse gliomas represent the most frequent primary brain tumours in adults. In the last years, landmark studies led to tremendous advances in terms of the knowledge of the molecular bases of gliomagenesis. This resulted in a paradigm shift in their classification. Regrettably, such advances have not yet corresponded to comparable improvements in terms of patient outcome. New approaches and therapies are compellingly needed. Method We performed a literature review for articles on the topic in PubMed, Google Scholar, and Web of Science until January 2022. Search keywords included “glioma”, “glioblastoma”, “tumour microenvironment”, “immunotherapy”, “targeted therapy”, and “radiomics”. Result This review will present the novelties in the classification system of diffuse gliomas, focusing on its molecular determinants with major prognostic and therapeutic significance. We will recapitulate progresses regarding potentially or already actionable alterations and proposed targeted therapeutical strategies. Another section will cover the glioma microenvironment and its exploitable therapeutical potential. Established and emerging aspects of immunotherapy in this field will be discussed. Lastly, we will discuss the potential of medical imaging in the field. Particularly, we will introduce the concepts of radiomics, radiogenomics, and the applications of artificial intelligence to them. Conclusion Diffuse gliomas show resistance to several molecularly targeted therapies and immunotherapies effective in other solid cancers. Glioma heterogeneity and the immunologically “cold” microenvironment have been invoked as possible reasons. Nonetheless, novel approaches can be beneficial in specific populations of glioma patients. In this complex interplay, medical imaging can reliably generate data at “-omics” level with predictive, theranostic, and/or prognostic purposes.