The escalating prevalence of obesity represents an increasing socioeconomic burden for international health care systems. So far, pharmacological anti-obesity therapies were overall incapable of tackling the obesity epidemic. The development of novel pharmacotherapies that improve systems metabolism in a safe yet efficient manner is of increasing global priority. Novel polypharmacological approaches, that are based either on adjunctive administration of several hormones or on combination of several hormones into single molecules, have shown a remarkable success in reversing metabolic alterations associated with the metabolic syndrome. The aim of this chapter is to summarize recent advances in preclinical and clinical approaches that employ novel combinations of leptin and other drugs, hormones, and biogenic peptides.