CREB, the cAMP response element binding protein, is a key transcriptional regulator of a large number of genes containing a CRE consensus sequence in their upstream regulatory regions. Mice with a hypomorphic allele of CREB that leads to a loss of the CREBalpha and delta isoforms and to an overexpression of the CREBbeta isoform are viable. Herein we report the generation of CREB null mice, which have all functional isoforms (CREBalpha, beta, and delta) inactivated. In contrast to the CREBalpha delta mice, CREB null mice are smaller than their littermates and die immediately after birth from respiratory distress. In brain, a strong reduction in the corpus callosum and the anterior commissures is observed. Furthermore, CREB null mice have an impaired fetal T cell development of the alpha beta lineage, which is not affected in CREBalpha delta mice on embryonic day 18.5. Overall thymic cellularity in CREB null mice is severely reduced affecting all developmental stages of the alpha beta T cell lineage. In contrast gamma delta T cell differentiation is normal in CREB mutant mice.