<p>High-risk neuroblastoma (HRNB) accounts for a disproportionately high percentage of cancer-related deaths among pediatric patients, despite intensive multimodal treatment. Current frontline therapy comprising chemotherapy, surgery, autologous stem cell transplantation (ASCT), radiation, immunotherapy, and tumor differentiation agents has improved survival rates; however, overall outcomes have plateaued. Refractory and relapsed cases are associated with even poorer prognoses, underscoring the limitations of existing treatment regimens. Additionally, treatment-related toxicities from intensive therapies pose significant risks to patients’ quality of life and long-term health, highlighting the need for novel therapeutic approaches. In response, recent efforts have focused on integrating new modalities into frontline therapy, such as anti-GD2 immunotherapy, iodine-131 (¹³¹I)-metaiodobenzylguanidine (MIBG) therapy, and targeted agents for patients with identifiable molecular mutations, alongside adding eflornithine as maintenance therapy. In parallel, advancements in treating refractory and relapsed neuroblastoma emphasize innovative approaches, including novel targeted therapies, immunotherapy, and radionucleotides. This review discusses both the current standard of care for high-risk neuroblastoma as well as focusing on emerging immunotherapy including cellular therapy in an effort to improve outcomes, both in terms of survival and treatment-related late effects. </p>