G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins. These proteins participate in virtually all physiological responses, are ubiquitously important for pathophysiological control, and are a major target for drug discovery. Class B GPCRs include receptors for major endocrine regulators, including calcitonin, amylin, parathyroid hormone, glucagon and the glucagon-like peptides, and these receptors have been targeted for the treatment of bone and metabolic disease. However, different ligands, acting at the same receptor can yield distinct outcomes, a phenomenon termed biased agonism. This creates both increased complexity and novel opportunity for drug discovery. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), display biased agonism and this can yield distinct physiological responses. Development of optimal treatments requires understanding of the molecular basis, and consequences of biased agonism. In this talk I will review our work identifying and quantifying biased agonism at class B GPCRs using the GLP-1R as the key exemplar and describe how we are now combining recent structural data with scanning mutagenesis to provide insights into the initiation and propagation of biased agonism.