Introduction Embryonal tumors with multilayered rosettes (ETMR) are rare but aggressive cancers, commonly occurring in children under three years of age. They are an under-recognized entity and the current WHO diagnostic evaluation can be challenging to implement in a timely manner to allow prompt treatment, particularly in resource limited healthcare settings. ETMRs also represent a therapeutic challenge as there are no uniform treatment protocols. Chemotherapy-only strategies may be employed aiming to avoid or delay the deleterious effects of radiation to the developing brain. Here, we describe two cases of ETMR from different healthcare settings, which were presented at the Society for Neuro-Oncology (SNO) Pediatric Molecular Tumor Board Quarterly Series (March 2022) to highlight and discuss the challenges for timely diagnosis and management. These cases highlight the heterogeneous responses to treatment, which remain unpredictable based on current knowledge. One patient died despite use of multimodality therapy including surgery, intensive chemotherapy, and radiotherapy. The second patient is a long-term survivor, treated with chemotherapy only after surgery. We discuss the minimal set of key pathological and molecular findings required in order to establish the timely diagnosis of ETMR, the role of different therapies, and future perspectives on the management of this rare and aggressive condition, with the aim of improving clinical outcomes.