G protein-coupled receptors (GPCRs) are the largest family of cell surface drug targets. Consequently, there is high interest in understanding the structure of members of this receptor superfamily and the molecular detail of how ligands and transducer proteins interact with them. Our laboratory has been applying single particle cryo-EM to determination of active GPCR structures, using minimally modified receptors. Our work has been principally focused on the class B GPCR subfamily that bind large peptide hormones and are well established clinical targets for the treatment of major disease, including migraine, irritable bowel syndrome, diabetes, obesity and neurodegeneration. Combining novel structural information with molecular pharmacology, biophysical studies and molecular dynamics simulations, we are gaining substantial insights into how ligands and accessory proteins interact with this receptor family to facilitate G protein coupling and downstream signaling.