In all species studied to date, growth hormone (GH) is released episodically. Traditionally, the regulation of this process was considered to be mediated by two hypothalamic hormones, growth hormone-releasing hormone (GHRH) and somatostatin (sst). More recently, we identified a new orphan G-protein-coupled receptor that causes episodic GH release upon activation by synthetic ligands. These ligands include the GH-releasing peptides (GHRPs) first described by Bowers and their small molecule mimetics such as L-692,429 and MK-0677. Site-directed mutagenesis of this GH secretagogue receptor (GHS-R) has defined key amino acid residues essential for binding and activation by the synthetic ligands. The GHS-R is not activated by GHRH or sst. It is expressed exclusively in the anterior pituitary lobe and central nervous system and although this new receptor does not belong to any of the known families of G-protein-coupled receptors, the GHS-R is highly conserved across species. The Puffer fish homolog, in common with the human GHS-R, is activated by the structurally distinct ligands GHRP-6, MK-0677 and L-163,540. Thus, the GHS-R ligand-binding pocket has apparently been conserved for at least 400 million years. Studies in humans suggest that production of an endogenous ligand declines during aging. For example, chronic treatment with the synthetic ligand MK-0677 reverses the age-related physiological changes in the GH/IGF-I (insulin-like growth factor I) axis of 70–94 year old subjects. Based on the localization of expression of GHS-R in the brain, reduced production of the natural ligand might also be involved in age-associated changes in cognition, memory, mood and behavior.