A minimal-model framework is that growth hormone (GH) secretion is controlled by an ensemble of interlinked peptides, namely, GH-releasing hormone (GHRH), somatostatin (SS), and ghrelin. Clinical studies, laboratory experiments, rare sporadic mutations, targeted gene silencing, and biomathematical models establish that at least three signals regulate GH secretion. A clarion implication of the concept of integrative control is that no one peptidic effector operates alone or can be adequately studied alone. A major unanswered question is how pathophysiology disrupts the core regulatory ensemble, thereby forcing relative GH and IGF-1 deficiency or excess. However, salient technical hurdles exist, namely, the lack of reliable experimental strategies and the paucity of validated analytical tools to distinguish the interlinked roles of GHRH, SS, and ghrelin. To address these significant obstacles requires administering peptide secretagogues in distinct combinations akin to the classical insulin/glucose clamp and implementing an analytical formalism to parse the interactive roles of GHRH, SS, and ghrelin objectively.