Next-generation sequencing (NGS) has revolutionized the diagnostic and clinical approach to central nervous system (CNS) tumors. By enabling comprehensive detection of single-nucleotide variants, gene fusions, copy number variations, and mutational signatures, NGS complements histopathology and immunohistochemistry, forming the basis of integrated diagnoses according to the 2021 WHO CNS classification and cIMPACT-NOW recommendations. Alongside DNA methylation profiling and copy number analysis, NGS has refined tumor taxonomy, allowing precise delineation of entities such as IDH-mutant gliomas, H3-altered diffuse gliomas, fusion-driven ependymomas, and embryonal tumors with specific genetic alterations. Clinically, NGS not only confirms diagnostic criteria but also provides prognostic information, for example, through CDKN2A/2B deletions or TERT promoter mutations, and identifies actionable targets such as BRAF V600E mutations, NTRK fusions, and ALK rearrangements, increasingly relevant for targeted and immunotherapies. Pediatric neuro-oncology particularly benefits from this approach, where fusion-driven and pathway-specific alterations critically guide treatment strategies. Despite the high value of broad genomic panels, cost and turnaround time considerations encourage the use of focused CNS-specific assays, often on FFPE-derived DNA/RNA.