Growth hormone (GH) is a key anabolic hormone that sustains healthy body composition in adulthood. Accordingly, alterations in the secretion of growth hormone (GH) relative to positive and negative energy balance maintain optimal heath. Herein, key peripheral signals modify central mechanisms that regulate the pulsatile release of GH. Of interest, orexigenic and anorexigenic factors are though to modulate the activity of hypothalamic neuronal populations that interact with primary GH pulse generators; somatostatin (SST) and GH releasing hormone (GHRH) expressing neurons. Our advent of a sensitive method to monitor the pulsatile production of GH release in mice has allowed incorporation of transgenic mouse models to further define these interactions. Moreover, this method has allowed repeat and accurate assessment of GH secretion at regular intervals throughout life in the mouse, thus permitting assessment of progressive changes in GH secretion prior to and following intervention. Measures provide valuable information to identify changes in pulse frequency and amplitude of GH release, and extrapolation of these measures offer key insights relating to the neuroendocrine regulation of GH secretion. In this seminar, I will discuss our recent progress that defines such mechanisms. Observations demonstrate key interactions between hypothalamic and pituitary regulators of GH secretion, and components of melanocortin system. Of interest, data highlight the role of neuropeptide Y (NPY) expressing neurons as prominent regulators of GH release in negative energy balance, while redefining the role of the melanocortin 4 receptor (MC4R) as a regulator of GH secretion following dietary induced weight gain. An extension of these observations provides renewed opportunities to define the role of GH as key regulator of energy homeostasis in heath and in disease.