Leptin is a 16-kDa cytokine hormone produced mainly by white adipose tissue (WAT), but also by skeletal muscle, the gastric mucosa, the placenta, and mammary epithelium. It is a pleiotropic hormone influencing not only energy balance, but also glycemic control, cognition, hematopoiesis, immune function, neuroendocrine function, and reproduction. In this review, an over-view of the current understanding of the role of leptin in the regulation of energy balance, glycemic control, and cognitive function is presented, and evidence supporting the notion that leptin may be the biochemical link mediating the homeostatic “harmony” of these metabolic and neurologic physiologies is examined. The underlying cause for the failure of leptin therapy in the clinic, and the ability of synthetic peptide amides encompassing a functional domain within the leptin molecule to overcome this failure, are discussed. Finally, the translational pathway that was taken to initially identify the functional epitope(s) in the leptin molecule, and then to improve the efficacy and pharmacokinetics of a series of biologically active synthetic peptide leptin mimetics, potentially targeting the clinical management of a number of unmet medical needs influenced by leptin biology, namely obesity, diabetes, dyslipidemia, and cognitive impairment, is described.