Class B1 G protein-coupled receptors (GPCRs) are peptide hormone activated receptors that mediate numerous physiological actions and are well validated therapeutic targets for type 2 diabetes and obesity. In recent years, engineered glucagon-like peptide 1 receptor (GLP-1R) agonists have transformed obesity management, while calcitonin and amylin receptor agonists are emerging as efficacious obesity drugs with a distinct mechanism of action. Moreover, numerous peptide and non-peptide agonists are in clinical development that target the GLP-1R or co-target the GLP-1R with other class B1 GPCRs. However, the ideal pharmacological profiles at individual receptors for mono-agonists, and the balance of activity at different receptors for multi-receptor agonists is still unknown. This talk will highlight how our lab is combining cryo-electron microscopy, pharmacological profiling and in vivo assays to understand how these class B1 GPCRs bind distinct ligands, how we can fine-tune receptor signalling at individual receptors or the balance of activity at distinct receptors in poly-agonists that activate more than one receptor, and how binding of individual ligands change receptor conformations to exhibit distinct signaling profiles with potential for differences in therapeutic efficacy.