Programmed cell death (PCD) is major concept in neurobiology and transcription factors are pivotal in switching on the nerve cell death program. More recently, the transcriptional control of programmed cell life (PCL) is beginning to be understood. This work began in studies of the activation of the CREB transcription factor in stroke models where it was shown that CREB is phosphorylated (and presumably activated) in neurons that survive this insult. In this review I will describe this data and also discuss the up-stream and down-stream pathways in this CREB neuroprotective transcriptional cassette. Finally, I will discuss studies showing that this CREB survival pathway may be inactivated by neurotoxins and genes involved in neurodegenerative disorders.