The phosphatidylinositol 3'-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the most potent prosurvival signaling cascades that is aberrantly activated in a variety of human cancers. Recent evidence demonstrates that pathological activation of Akt also frequently occurs in neuroblastoma and correlates with poor prognosis. Thus, therapeutic targeting of PI3K/Akt/mTOR may present a promising approach for the design of molecular targeted therapies in neuroblastoma. Several strategies have in recent years been developed to interfere with distinct components of PI3K/Akt/mTOR signaling at different levels of the cascade. It will be subject to future studies to evaluate which of these compounds are most suitable for the treatment of neuroblastoma. Eventually, PI3K/Akt/mTOR targeting agents may open novel perspectives to improve the poor prognosis of patients with neuroblastoma especially in advanced stages of the disease.