Purpose This retrospective study aims to show a real-life single-center experience with clinical management of relapsed pediatric ependymomas using results from comprehensive molecular profiling. Methods Eight relapsed ependymomas were tested by whole exome sequencing, RNA sequencing, phosphoproteomic arrays, array comparative genome hybridization, and immunohistochemistry staining for PD-L1 expression and treated with an individualized approach implementing targeted inhibitors, immunotherapy, antiangiogenic metronomic treatment, or other agents. Treatment efficacy was evaluated using progression-free survival (PFS), overall survival (OS), survival after relapse (SAR), and PFS ratios. Results Genomic analyses did not reveal any therapeutically actionable alterations. Surgery remained the cornerstone of patient treatment, supplemented by adjuvant radiotherapy. Empiric agents were chosen quite frequently, often involving drug repurposing. In six patients, prolonged PFS after relapse was seen because of immunotherapy, MEMMAT, or empiric agents and is reflected in the PFS ratio ≥ 1. The 5-year OS was 88%, the 10-year OS was 73%, the 2-year SAR was 88%, and the 5-year SAR was 66%. Conclusion We demonstrated the feasibility and good safety profile. Promising was the effect of immunotherapy on ZFTA-positive ependymomas. However, further research is required to establish the most effective approach for achieving sustained remission in these patients.