The mammalian target of rapamycin (mTOR)/p70S6 kinase (S6K) pathway plays an important role in brain‐derived neurotrophic factor (BDNF)‐mediated protein synthesis and neuroplasticity. Although many aspects of neuronal function are regulated by intracellular calcium ([Ca2+]i) and calmodulin (CaM), their functions in BDNF‐induced phosphorylation of p70S6K and protein synthesis are largely unknown. Here, we report that BDNF, via TrkB‐dependent activation of mTOR, induces sustained phosphorylation of p70S6K at Thr389 and Thr421/Ser424. BDNF‐induced phosphorylation at Thr389 was dependent on PI3 kinase but independent of ERK‐MAPK. The previously identified MAPK phosphorylation site at Thr421/Ser424 required both PI3K and MAPK in BDNF‐stimulated neurons. Furthermore, we found that the reduction in [Ca2+]i, but not extracellular calcium, blocked the BDNF‐induced phosphorylation of p70S6K at both sites. Inhibition of CaM by W13 also blocked p70S6K phosphorylation. In correlation, W13 inhibited BDNF‐induced local dendritic protein synthesis. Interestingly, sustained elevation of [Ca2+]i by membrane depolarization antagonized the BDNF‐induced p70S6K phosphorylation. Finally, the BDNF‐induced p70S6K phosphorylation did not require the increase of calcium level through either extracellular influx or PLC‐mediated intracellular calcium release. Collectively, these results indicate that the basal level of intracellular calcium gates BDNF‐induced activation of p70S6K and protein synthesis through CaM. © 2009 Wiley‐Liss, Inc.