Glucagon-like peptide-1 receptor (GLP-1R), a class B1 G protein-coupled receptor, plays critical roles in glucose homeostasis. Recent structural pharmacology studies using cryogenic electron microscopy, X-ray crystallography, mass spectrometry, and functional analyses, have provided valuable insights into its activation by endogenous hormones and mono- or dual agonists like semaglutide and tirzepatide, highly effective in treating type 2 diabetes and obesity. They highlight significant conformational changes in the extracellular and transmembrane domains of GLP-1R that drive receptor activation and downstream signal transduction. Additionally, allosteric modulators, supported by emerging structural information, show great promises as an alternative strategy. Future research investigating unexplored effector interactions, biased signaling, weight rebound mechanisms, and personalized therapy strategies will be critical for developing better therapeutic agents targeting GLP-1R.