Epilepsy is a common neurologic disorder yet no treatments aimed at preventing epilepsy have been developed. Several molecules including genes containing cAMP response elements (CREs) in their promoters have been identified that contribute to the development of epilepsy, a process called epileptogenesis. When phosphorylated cAMP response element binding protein (CREB) increases transcription from CRE regulated promoters. CREB phosphorylation is increased in rodent epilepsy models, and in the seizure onset region of humans with medically intractable epilepsy (Rakhade et al., 2005; Lee et al., 2007; Lund et al., 2008). Here we show that mice with decreased CREB levels (CREB(α∆) mutants) have a ~50% reduction in spontaneous seizures following pilocarpine induced status epilepticus (SE) and require more stimulation to electrically kindle. Following SE, brain derived neurotrophic factor (BDNF) and inducible cAMP early repressor (ICER) mRNAs are differentially up-regulated in the hippocampus and cortex of the CREB(α∆) mutants compared to wild-type mice, which may be contributing to differences in the severity of epilepsy. In contrast, we found no difference in KCC2 mRNA levels between the CREB(α∆) and wild-type mice after SE. The mechanism by which BDNF and ICER mRNAs increase specifically in the CREB(α∆) compared to wild-type mice following SE is not known. We did, however, find an increase in specific cAMP response element modulator (CREM) mRNA transcripts in the CREB(α∆) mutants that might be responsible for the differential regulation of BDNF and ICER after SE. Altering CREB activity following a neurologic insult provides a therapeutic strategy for modifying epileptogenesis.