Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor in children. High-risk and refractory NB signifies poor prognosis, and is difficult to treat due to the lack of response to current therapies and aggressive disease progression. Novel drugs and alternative treatments are being investigated for patients with refractory or high-risk NB. However, finding an effective treatment strategy for these patients continues to be a major challenge due to a myriad of complex mechanisms that promote NB progression, including increased tumor growth and metastasis, and resistance to treatments. Previous studies have shown that MycN, a prognostic indicator for advanced and high-risk NB, regulates the expression of TRPM7, a calcium-permeable ion channel that plays a role in NB progression. The current research investigated the mechanism by which TRPM7 regulates NB progression. The results show that TRPM7 expression is significantly increased in high-risk and drug resistant NB, and down-regulating TRPM7 sensitizes NB cells to chemotherapeutic agents and induces cell death. The preliminary data also demonstrate that TRPM7 reside in the membrane of vesicles that are mobilized to the cleavage furrow during mitosis. Accordingly, inhibition of TRPM7 prevented the mobilization of TRPM7 vesicles, inhibited mitosis, and led to multi-nucleated cells and eventually cell death. The results from this study suggest that TRPM7 plays a critical role in regulating proper mitotic progression, and promotes drug resistance in NB. Accordingly, loss of TRPM7 activity sensitizes drug resistant NB to chemotherapeutic drugs by inducing mitotic catastrophe and cell death.