Neuroblastoma, as well defined by Willis,1 is an embryonal tumor of neural crest origin. Tumors of the neuroblastoma group include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. We believe that all ganglioneuromas were once neuroblastomas in the early stage of tumor development.1,2 They are collectively called peripheral neuroblastic tumors (pNTs) and are known to present with a wide range of clinical behavior, from spontaneous regression and tumor maturation to aggressive progression that is refractory to intensive treatment. Recent advances in research indicate that molecular and/or genomic properties of individual tumors are closely associated with their unique clinical behaviors.3–5 During the past several decades, histopathologic analyses of pNTs have provided invaluable information for predicting prognosis and determining therapy stratification. The origin of International Neuroblastoma Pathology Classification (INPC) dates to the 1984 article by Shimada et al6 that first introduced the age-linked pathology classification system. Since then, the Shimada system has laid the foundation for the current INPC.2,7 The INPC, as a single prognostic parameter, clearly defines clinically aggressive and nonaggressive groups of pNTs.7,8 The INPC, distinguishing favorable histology (FH) and unfavorable histology (UH) groups, defines four categories of pNTs: neuroblastoma (Schwannian stroma poor); ganglioneuroblastoma, intermixed (Schwannian stroma rich); ganglioneuroma (Schwannian stroma dominant); and ganglioneuroblastoma, nodular (composite, Schwannian stroma rich/stroma dominant and stroma poor).2 Cases in the ganglioneuroblastoma, intermixed and ganglioneuroma categories are always classified into the FH group, and the patients enjoy excellent clinical outcomes.9 Patients with disease in the neuroblastoma and ganglioneuroblastoma, nodular categories are classified into either the FH group or UH group on the basis of age-linked evaluation (0 to 18 months, 18 to 60 months, and ≥ 60 months) of neuroblastic differentiation grade (undifferentiated, poorly differentiated, and differentiating) and Mitosis-Karyorrhexis index (low: < 100/5,000 cells; intermediate 100 to 200/5,000 cells; and high: ≥ 200/5,000 cells) of the individual neuroblastoma tumors or neuroblastoma component of ganglioneuroblastoma, nodular tumors.2,7,8,10,11 Whereas survival of patients with FH pNT is excellent (> 90%), survival of patients with UH pNT has only incrementally improved over the years and currently remains approximately 40% to 50%.7,8,10 This seems to be mainly because we have had a limited idea of what molecular mechanism underlies the therapy-resistant behavior of UH tumors. These observations have led us to seek additional immunohistochemical biomarkers that are tightly associated with aggressive behaviors—that is, unresponsiveness or resistance to the current intensive multimodal therapy—of certain UH tumors. To address this problem, we and others have sought and identified the expression of potentially drug-targetable proteins that are responsible for their aggressive progression in the UH group. When we seek such biomarkers, they are preferably actionable/ druggable by existing pharmaceutical agents, US Food and Drug Administration approved, or currently tested in human clinical trials. If we could effectively neutralize the activity of such targets with specific drugs, then survival of UH patients as a whole would substantially improve.