Neuroblastoma is an aggressive pediatric tumor condition derived from neural crest cells that typically affect infants and children under the age of five. It can often originate in the adrenal glands but can also develop in the sympathetic nervous system. G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases have been shown in recent research to have a vital role in the progression of neuroblastoma. GPCR-RTK crosstalk stimulates signaling pathways such as MAP kinase, and the activation of the GPCR-AKT signaling pathway plays a critical role in neuroblastoma progression by promoting cell growth, survival, and resistance to apoptosis through complex interactions with insulin signaling pathways. ALK (Anaplastic lymphoma kinase), a member of the RTK family, and any mutations can lead to oncogenic signaling and resistance to targeted therapy in neuroblastoma. By interfering with cellular signaling via novel therapeutic strategies by selective RET inhibitors, ALK inhibitors, and Trk-specific inhibitors may be able to reduce the prevalence of neuroblastoma. Understanding the complicated signaling relationships between GPCRs, RTKs, and the insulin pathway is critical when developing new cancer treatments. The integration of these signaling networks offers promising avenues for enhancing the effectiveness of existing treatments and improving patient outcomes in neuroblastoma.