Our laboratory has applied single particle cryo-EM to determine GPCR structures in complex with the canonical transducer, heterotrimeric G proteins, with an emphasis on class B1 peptide hormone GPCRs that are important targets for major disease including diabetes, obesity and osteoporosis. We have applied both Volta phase-plate (VPP) and conventional transmission electron microscopy (CTEM) cryo-EM data collection to derive structures of GPCRs as active complexes of agonist, receptor and heterotrimeric G proteins. Solution of multiple class B1 GPCR actives structures (calcitonin receptor, CTR; glucagon-like peptide-1 receptor, GLP-1R; calcitonin gene-related peptide receptor, CGRPR; adrenomedullin 1 and 2 receptors, AM1R and AM2R, respectively; corticotropin releasing factor 1 receptor, CRF1R, pituitary adenylate cyclase activating peptide 1 receptor, PAC1R; and secretin receptor, SecR) revealed common macromolecular changes associated with G protein coupling that included a profound kinking of TM6 around the class B GPCR conserved Pro-X-X-Gly motif (required for the outward movement of the base of TM6 to accommodate G protein binding), and outward or lateral movements of the upper segments of TM7 and TM1, bending around conserved Gly residues. The GLP-1R has also been solved with different peptide agonists, exendin-P5, exendin-4 and oxyntomodulin, that exhibit biased signalling, as well as a small molecule agonist, TT-OAD2. The TM1/ECL3 domain in the GLP-1 receptor was the site of largest conformational variance between the ExP5 and GLP-1 bound GLP-1R structures and was linked to distinct efficacy for Gs signalling. The small molecule bound structure revealed an unexpected site of interaction and new insight into how class B GPCRs may be activated. The CGRPR, AM1R and AM2R are GPCR:RAMP heteromers (CLR:RAMP1, CLR:RAMP2 and CLR:RAMP3, respectively) where the structure revealed an unexpected interface for RAMP-GPCR interaction, along with insights into the allosteric regulation of GPCR function. In some structures, multiple high resolution confomers have been obtained that provide insight into conformational dynamics of these complexes. This work has provided major insight into how peptides interact with their receptors to drive G protein mediated signalling.