Survival rates for metastatic neuroblastoma remain poor, despite significant increase in the intensity of therapy. Although it represents approximately 7% of pediatric cancer, neuroblastoma accounts for approximately 15% of childhood cancer deaths. Thus, novel approaches to enhance neuroblastoma chemotherapy sensitivity and prevent or bypass chemoresistance are required. Disruption of the p53 pathway is a common mechanism leading to defects in apoptosis in cancer cells. Increasing evidence suggests that the p53 pathway may be inactivated in neuroblastoma. Inactivation of the p53 pathway occurs most commonly at the time of relapse, and probably contributes to chemoresistance. The p53 family proteins, p73 and p63, can also induce apoptosis, and early studies suggest that p73 may be important in neuroblastoma pathogenesis and response to treatment. This article focuses on current therapies and novel drugs targeting p53 and p73 signaling pathways in neuroblastoma. Understanding the balance between the p53 family proteins in neuroblastoma and how their expression and activity are regulated will hopefully lead to the discovery of agents that target these pathways to induce neuroblastoma cell death, alone or in combination with chemotherapies.