High-risk neuroblastoma remains a therapeutic challenge for pediatric oncologists. It is becoming increasingly evident that conventional chemotherapeutics are approaching or perhaps have already attained their maximum therapeutic potential. The focus of this review is to summarize current therapies and bring to light some of the novel strategies for treating high-risk neuroblastoma. These rationally designed therapies include molecular- and immune-targeted agents in an attempt to exploit the biology of the neuroblastoma cell. These novel therapies are likely to pose a whole new set of challenges and questions and emphasize the need for continued enrollment of patients in therapeutic studies.