Many complex diseases have historically proven to be defiant to the best mono-therapeutic approaches. Several examples of combination therapies have largely overcome such challenges, notably for the treatment of severe hypertension and tuberculosis. Obesity and its consequences, such as type 2 diabetes, have proven to be equally resistant to therapeutic approaches based on single medicines. Proper management of type 2 diabetes often requires adjunctive medications, and the recent registration of a few compound mixtures has set the precedent for combinatorial treatment of obesity. On the other hand, double or triple therapeutic combinations are more difficult to advance to regulatory approval than single molecules. More recently, several classes of novel unimolecular combination therapeutics have emerged with superior efficacy than currently prescribed options and pose the potential to reverse obesity and type 2 diabetes. Here, we summarize the discovery, pre-clinical validation, and first clinical test of such peptide hormone poly-agonist drug candidates.