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One of the most active topics in the growth hormone-IGF-1 field is that of the so-called growth hormone secretagogues (GHS). At a time when the isolation of GHRH had not occurred, the GHS were developed as artificial tools to release GH. The interest in these groups of compounds was rekindled when it was realized that they were not surrogates of GHRH nor were they acting through the modulation of the release of either GHRH or somatostatin. With the subsequent cloning of the specific receptor of GHS, and today of the natural ligand for that receptor, named ghrelin, it soon become clear that GHS and the GHS-receptor were part of a new physiological system involved in GH regulation. The dual control of GH secretion became a trinity. GHS releases GH when administered by any route--oral, iv, sc, and even transdermally-with a surprising potency and reproductivity. In addition, GHS when administered together with GHRH exert a synergistic action on GH secretion and that combined administration is the most potent GH releaser to date. Clinical studies have demonstrated that the GHS-GHRH administration may be considered the new "gold standard" test of GH reserve in humans, as the GH secretion so elicited is not altered by gender, adiposity, or age. The combined administration of GHRH plus GHS is able to discriminate between healthy subjects and patients with adult GH deficiency, suggesting a considerable utility in the clinical setting.