Chemoresistance and increased expression of TrkB and brain-derived neurotrophic factor (BDNF) are biomarkers of poor prognosis in tumors from patients with neuroblastoma (NB). Previously, we found BDNF activation of TrkB through PI3K/Akt protects NB from etoposide/cisplatin-induced cell death. In this study, the role of Bim, a proapoptotic protein, was investigated. Bim was involved in paclitaxel but not etoposide or cisplatin-induced cell death in NB cells. Pharmacological and genetic studies showed that BDNF-induced decreases in Bim were regulated by MAPK and not PI3K/Akt pathway. Both MAPK and PI3K pathways were involved in BDNF protection of NB cells from paclitaxel-induced cell death, while PI3K predominantly mediated BDNF protection of NB cells from etoposide or cisplatin-induced cell death. These data indicate that different chemotherapeutic drugs induce distinct death pathways and growth factors utilize different signal transduction pathways to modulate the effects of chemotherapy on cells.