Neuroblastoma (NB) ranks as the first most prevalent extra-cranial malignant tumor of childhood, contributing to 10% of pediatric cancer-related fatalities. High-risk NB patients often encounter metastasis, and despite aggressive multimodal therapies, long-term survival remains discouraging below 50%. This challenge predominantly arises from the emergence of treatment resistance, inherent or acquired in primary tumors, relapses, or metastases—primarily found within the bone marrow. Consequently, there is an urgent demand for innovative and refined treatment strategies. To address these challenges, our lab group has successfully pioneered developing in vivo and ex vivo models based on orthotopic NB patient-derived xenograft (PDX) models within a humanized bone marrow niche. We have also created 3D organoids of NB cells, all of which enable the exploration of vulnerabilities within a clinically relevant drug regimen. Integrating these models with cutting-edge techniques and state-of-the-art high-throughput technologies promises to provide profound insights into the mechanisms driving drug resistance and metastasis in cancer cells.