Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 multispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these multispecific molecules reduce body weight (BW) and improve many metabolic parameters. Overall, these GIPR-Ab/GLP-1 molecules promote BW loss, and they may be used for treating obesity.