Administration of chemically synthesized ghrelin peptide has been shown to increase food intake and body adiposity in most species. However, the biological role of endogenous ghrelin in the molecular control of energy metabolism is far less understood. Mice deficient for either ghrelin or its receptor (the growth hormone secretagogue receptor, GHS-R1a) seem to exhibit enhanced protection against high fat diet induced obesity, but do not show a substantial metabolic phenotype on a standard diet. Here we present the first mouse mutant lacking both, ghrelin and the ghrelin receptor. We demonstrate that simultaneous genetic disruption of both genes of the ghrelin system leads to an enhanced energy metabolism phenotype. Ghrelin/ghrelin receptor double knock out (dKO) mice exhibit decreased body weight, increased energy expenditure and increased motor activity on a standard diet without exposure to a high caloric environment. Mice on the same genetic background lacking either the ghrelin or the ghrelin receptor gene did not exhibit such a phenotype on standard chow, thereby confirming earlier reports. No differences in food intake, meal pattern or lean mass were observed between dKO, ghrelin deficient, ghrelin receptor deficient and wild type control mice. Only dKO showed lower plasma leptin and a slight decrease in body length. In summary, simultaneous deletion of ghrelin and its receptor enhances the metabolic phenotype of single gene deficient mice in comparison with wild type mice, possibly suggesting the existence of additional, as of yet unknown, molecular components of the endogenous ghrelin system.