Basic fibroblast growth factor (Fgf2) is required for the generation of founder cells within the dorsal pseudostratified ventricular epithelium, which will generate the cerebral cortex, but the ganglionic eminences are not affected. We report here that the Fgf2 null mutant mice show an approximately 40% decrease in cortical glutamatergic pyramidal neurons. In contrast, no change in pyramidal or granule cell number is detected in the hippocampus of Fgf2 -/- mice. In addition, the soma of the pyramidal cells in the frontal and parietal cortices are smaller in Fgf2 knock-out mice. The decrease in the number and size of glutamatergic neuronal population affects all cortical layers but is restricted to the frontal and parietal cortices without any change in the occipital cortex, indicating that Fgf2 is necessary to regulate cell number and size in the anterior cerebral cortex. In contrast to pyramidal neurons, cortical GABA interneurons are unaffected by the lack of Fgf2. The resulting imbalance between the excitatory and inhibitory neurotransmission in the cerebral cortex is reflected by an increased duration of sleep when the animals receive a GABA receptor agonist. Thus, Fgf2 signaling may contribute to the regional specification of the cerebral cortex and may play a role in increasing the size of anterior cortical regions during vertebrate evolution.