Background: Along with the global increase in obesity, type 2 diabetes continues to spread worldwide. Thus, safe and effective treatment options are urgently needed because nonpharmacological treatment options, including lifestyle changes in diet and physical activity, fail to achieve sustained weight loss and glycemic control. Objectives: An overview of established therapeutic options in the treatment of obesity is presented with a focus on the discovery and translational relevance of new polyagonist-based therapies. Materials and methods: Recently published trials in the development and application of monomeric peptide-based polyagonists and peptide-based transport of steroid and thyroid hormones to treat obesity and diabetes are summarized and assessed. Results: Currently available pharmacological attempts to treat obesity have limited success with notable adverse effects. More promising are novel unimolecular hormonal polyagonists that have the unique potential to reverse obesity and diabetes in animal models. These activate up to three receptors with similar affinity. Beneficial effects on body weight and blood sugar levels in animals have been observed in preclinical research with a GLP-1/glucagon coagonist (GLP: glucagon-like peptide), a GLP-1/GIP coagonist (GIP: glucose-dependent insulinotropic polypeptide), and a GLP-1/GIP/glucagon triagonist. Similar positive effects could be demonstrated for steroid and thyroid hormones which are transported to specific tissues using a peptide transport molecule. Particularly promising are GLP-1/estrogen and glucagon/T3 (triiodothyronine). Conclusions: This article provides an overview of established therapeutic options in the treatment of obesity and focuses on the discovery and translational relevance of new polyagonist-based therapies.