The glucagon subfamily of class B G protein-coupled receptors (GPCRs) has been proposed to be a crucial drug target for the tretmaent of type 2 diabetes. The challenges associated with determining the crystal structures of class B GPCRs relate to their large amino termini and the lack of available small molecule ligands to stabilize the receptor proteins. Following our discovery of non-peptidic agonists for glucagon-like peptide-1 receptor (GLP-1R) that have therapeutic effects, we initiated collaborative efforts in structural biology and recently solved the three-dimensional (3D) structure of the human glucagon receptor (GCGR) 7-transmembrane domain, providing in-depth information about the underlying signaling mechanisms. In this review, some key milestones in this endeavor are highlighted, including discoveries of small molecule ligands, their roles in receptor crystallization, conformational changes in transmembrane domains (TMDs) upon activation and structure-activity relationship analyses.