Simple SummaryChildren affected by high-risk tumors receive aggressive standard therapies that significantly improve their survival. Despite this, they have a low quality of life, suffer from life-threatening side effects, and a still-relevant number of them show resistance to therapy and develop fatal relapses. Immunotherapy showed exciting results and is now a promising treatment for cancer patients; targeting B7-H3 fits this scenario. B7-H3 is expressed by many cancers, promotes their growth, and blocks the antitumor responses mediated by cells of the immune system. Promising preclinical results were obtained using antibodies or genetically engineered T lymphocytes recognizing B7-H3 and, currently, different clinical trials are ongoing. Hopefully, the targeting of B7-H3 will help cure adult and pediatric cancer patients.AbstractB7-H3 is a 4Ig transmembrane protein that emerged as a tumor-associated antigen in neuroblastoma. It belongs to the B7 family, shows an immunoregulatory role toward NK and T cells, and, therefore, has been included in the growing family of immune checkpoints. Besides neuroblastoma, B7-H3 is expressed by many pediatric cancers including tumors of the central nervous system, sarcomas, and acute myeloid leukemia. In children, particularly those affected by solid tumors, the therapeutic protocols are aggressive and cause important life-threatening side effects. Moreover, despite the improved survival observed in the last decade, a relevant number of patients show therapy resistance and fatal relapses. Immunotherapy represents a new frontier in the cure of cancer patients and the targeting of tumor antigens or immune checkpoints blockade showed exciting results in adults. In this encouraging scenario, researchers and clinicians are exploring the possibility to use immunotherapeutics targeting B7-H3; these include mAbs and chimeric antigen receptor T-cells (CAR-T). These tools are rapidly evolving to improve the efficacy and decrease the unwanted side effects; drug-conjugated mAbs, bi–tri-specific mAbs or CAR-T, and, very recently, NK cell engagers (NKCE), tetra-specific molecules engaging a tumor-associated antigen and NK cells, have been generated. Preclinical data are promising, and clinical trials are ongoing. Hopefully, the B7-H3 targeting will provide important benefits to cancer patients.