To investigate the role of serotonin 2C receptors (2CR), which are expressed only in the CNS, in the satiating actions of the gut peptides cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1), we examined (1) the effect of null mutations of serotonin 2CR (2CR KO) on the eating-inhibitory potencies of dark-onset intraperitoneal (IP) injections of 0.9, 1.7 or 3.5 nmol/kg (1, 2, or 4 µg/kg) CCK and 100, 200 and 400 nmol/kg (33, 66 or 132 µg/kg) GLP-1, and (2) the effects of IP injections of 1.7 nmol//kg CCK and 100 nmol/kg GLP-1 on neuronal activation in the brain, as measured by c-Fos expression. All CCK and GLP-1 doses decreased 30-min food intake in wild type (WT) mice, but none of them did in 2CR KO mice. CCK increased the number of cells expressing c-Fos in the nucleus tractus solitarii (NTS) of WT, but not 2CR KO mice. CCK induced similar degrees of c-Fos expression in the paraventricular (PVN) and arcuate (Arc) nuclei of the hypothalamus of both genotypes. GLP-1, on the other hand, increased c-Fos expression similarly in the NTS of both genotypes, and increased c-Fos expression more in the PVN and Arc of 2CR KO mice, but not WT mice. These results indicate that serotonin signaling via serotonin 2CR is necessary for the full satiating effects of CCK and GLP-1. In addition, they suggest that the satiating effects of the two peptides are mediated by different neural mechanisms.