High-grade gliomas (HGGs) are the most malignant types of CNS tumour which occur in both adults and children. While current treatment involves a multimodal approach, combining radiation and chemotherapy for both adult and paediatric gliomas, the 5-year survival rate is under 20% for both populations, underscoring an urgent need for novel therapies. Recent studies have shed light on common and unique genetic alterations that underpin adult and paediatric gliomas, raising the speculation that therapies targeting these specific drivers may shed light on new therapeutic options. To test this proposition, we conducted an integrated genomic analysis comprising genomic, transcriptomic and functional dependency (drug, CRISPR screen) profiling to identify targetable drivers of growth in paediatric (pHGG) and adult HGGs (aHGG). Comparative assessment of genomic and transcriptomic features of pHGG and aHGG cell lines revealed that pHGG harboured distinct alterations in the histone H3F3A and HIST1H3B genes and were defined by enrichment of neuronal developmental pathway gene expression signatures. Consistent with this, high throughput drug screens showed that pHGGs exhibited heightened sensitivity to epigenetic therapies. In contrast, adult HGG samples harboured mutations in components of receptor tyrosine kinase (RTK) signalling pathways, such as EGFR and PTEN and were preferentially sensitive towards RTK targeted inhibitors. Most strikingly, using both genetic and pharmacological perturbance, we uncovered a unique dependency to the anti-apoptotic BCL-2 family member, MCL-1 in pHGG. Integration of functional dependency with whole transcriptomic data across the adult and paediatric glioma cohorts revealed that MCL-1 dependency was highly correlated with low expression of other BCL-2 family members. Collectively, this study identifies MCL-1 as a new therapeutic target for pHGG patients with low BCL2L1 expression and more broadly highlights the power of integrative genomics to identify biomarker-enabled therapeutic strategies.