Neurotrophins regulate neuronal survival, differentiation, and synaptic function. To understand how neurotrophins elicit such diverse responses, we elucidated signaling pathways by which brain-derived neurotrophic factor (BDNF) activates gene expression in cultured neurons and hippocampal slices. We found, unexpectedly, that the transcription factor cyclic AMP response element-binding protein (CREB) is an important regulator of BDNF-induced gene expression. Exposure of neurons to BDNF stimulates CREB phosphorylation and activation via at least two signaling pathways: by a calcium/calmodulin-dependent kinase IV (CaMKIV)-regulated pathway that is activated by the release of intracellular calcium and by a Ras-dependent pathway. These findings reveal a previously unrecognized, CaMK-dependent mechanism by which neurotrophins activate CREB and suggest that CREB plays a central role in mediating neurotrophin responses in neurons.