Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut–brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.