G-protein-coupled receptors (GPCRs) are crucial for physiological responses to hormones, neurotransmitters, and environmental stimuli, making them important therapeutic targets. Recent high-resolution structural studies have provided insights into GPCR activation and constitutive activity. The structures of ligand-activated GPCRs, including the human β2-adrenergic receptor (β2AR), avian β1AR, human A2A adenosine receptor, and bovine rhodopsin, have been determined. These structures reveal the molecular mechanisms of GPCR activation and highlight differences in their extracellular and cytoplasmic surfaces. The extracellular surfaces of these structures show the molecular basis for antagonist and inverse-agonist ligand recognition. Differences in interactions involving conserved residues at the cytoplasmic surface explain varying levels of agonist-independent basal G-protein coupling activity. The structures of opsin and active rhodopsin reveal key conformational changes during GPCR activation. Despite their structural similarities, GPCRs have diverse signaling behaviors, including constitutive activity and G-protein-independent signaling. The structures of GPCRs in their inactive states provide insights into their functional properties and the role of ligand binding in modulating conformational changes. The study of GPCR structures has implications for drug discovery, as it helps in understanding the ligand efficacy and the structural basis of GPCR function. The challenges in obtaining GPCR structures include low expression levels, thermal instability, and proteolytic susceptibility. Recent advances in structural biology have enabled the determination of GPCR structures, providing a foundation for understanding their complex functional behavior. The structures of GPCRs in their inactive states reveal the importance of conformational changes in their activation and signaling. The study of GPCR structures has significant implications for drug discovery and the development of targeted therapies.G-protein-coupled receptors (GPCRs) are crucial for physiological responses to hormones, neurotransmitters, and environmental stimuli, making them important therapeutic targets. Recent high-resolution structural studies have provided insights into GPCR activation and constitutive activity. The structures of ligand-activated GPCRs, including the human β2-adrenergic receptor (β2AR), avian β1AR, human A2A adenosine receptor, and bovine rhodopsin, have been determined. These structures reveal the molecular mechanisms of GPCR activation and highlight differences in their extracellular and cytoplasmic surfaces. The extracellular surfaces of these structures show the molecular basis for antagonist and inverse-agonist ligand recognition. Differences in interactions involving conserved residues at the cytoplasmic surface explain varying levels of agonist-independent basal G-protein coupling activity. The structures of opsin and active rhodopsin reveal key conformational changes during GPCR activation. Despite their structural similarities, GPCRs have diverse signaling behaviors, including constitutive activity and G-protein-independent signaling. The structures of GPCRs in their inactive states provide insights into their functional properties and the role of ligand binding in modulating conformational changes. The study of GPCR structures has implications for drug discovery, as it helps in understanding the ligand efficacy and the structural basis of GPCR function. The challenges in obtaining GPCR structures include low expression levels, thermal instability, and proteolytic susceptibility. Recent advances in structural biology have enabled the determination of GPCR structures, providing a foundation for understanding their complex functional behavior. The structures of GPCRs in their inactive states reveal the importance of conformational changes in their activation and signaling. The study of GPCR structures has significant implications for drug discovery and the development of targeted therapies.