Our understanding of the biologic basis of neuroblastoma, the genetic heterogeneity of this malignancy and the role of host factors has expanded significantly in recent years. In this review, we highlight current and future risk-based treatment approaches and discuss the opportunities and challenges of selecting optimal therapies for specific patient subsets. Significant progress has been made in understanding neuroblastoma predisposition and new approaches have been taken to treatment of this disease. Although survival remains poor for patients with high-risk neuroblastoma, current-era therapy has improved outcomes. Integration of new prognostic markers into neuroblastoma classification systems will allow more precise risk classification and refined treatment assignment. Promising treatments that include targeted therapies as well as immunotherapeutics are being evaluated in clinical trials, and new predictive biomarkers are being developed. As our understanding of neuroblastoma biology deepens, our approaches to therapy for this disease continue to evolve. Improved risk stratification and the use of predictive biomarkers will aid in treatment selection for patients with neuroblastoma, and it is expected that future treatments will be associated with greater efficacy and less toxicity.