A range of molecules control nerve-cell survival in the brain. Many of these molecules might be neuroprotective through activation of the transcription factor cAMP-response-element-binding protein (CREB). Activation of CREB, by phosphorylation of Ser133, occurs in brain-damage-resistant hippocampal dentate granule cells and is triggered by neuroprotective environmental stimulation. In addition, the Akt neuroprotective signaling pathway activates CREB, and CREB synthesis and phosphorylation promote the survival of many cells, including neurons, in vitro. Thus, CREB might be responsible for programmed nerve-cell survival. Studies investigating its role in the brain are now required to confirm these in vitro results, and the downstream survival genes, whose expression is activated by CREB in neurons, need to be identified.