G-protein-coupled receptors (GPCRs) are crucial for mediating physiological responses to hormones, neurotransmitters, and environmental stimuli, making them potential therapeutic targets for a wide range of diseases. Recent advances in structural biology have provided insights into the molecular mechanisms of GPCR activation and constitutive activity. The first crystal structures of ligand-activated GPCRs, including the human β2 adrenergic receptor (β2AR), avian β1AR, and human A2A adenosine receptor, have been solved, along with the structures of opsin and an active form of rhodopsin. These structures reveal the molecular underpinnings of ligand recognition and the differences in cytoplasmic surface interactions that contribute to varying levels of constitutive activity among receptors. The structures also show that GPCRs can support a wide variety of ligand-binding modes, and that specific ligands can have different relative efficacies for different signaling pathways. Despite these advances, many challenges remain in understanding the structural basis of GPCR function, particularly in capturing the true active state of GPCRs. Future research should focus on developing methods to obtain structures of receptors bound to agonists and exploring the conformational dynamics of GPCRs using solution-based or membrane-compatible biophysical techniques.G-protein-coupled receptors (GPCRs) are crucial for mediating physiological responses to hormones, neurotransmitters, and environmental stimuli, making them potential therapeutic targets for a wide range of diseases. Recent advances in structural biology have provided insights into the molecular mechanisms of GPCR activation and constitutive activity. The first crystal structures of ligand-activated GPCRs, including the human β2 adrenergic receptor (β2AR), avian β1AR, and human A2A adenosine receptor, have been solved, along with the structures of opsin and an active form of rhodopsin. These structures reveal the molecular underpinnings of ligand recognition and the differences in cytoplasmic surface interactions that contribute to varying levels of constitutive activity among receptors. The structures also show that GPCRs can support a wide variety of ligand-binding modes, and that specific ligands can have different relative efficacies for different signaling pathways. Despite these advances, many challenges remain in understanding the structural basis of GPCR function, particularly in capturing the true active state of GPCRs. Future research should focus on developing methods to obtain structures of receptors bound to agonists and exploring the conformational dynamics of GPCRs using solution-based or membrane-compatible biophysical techniques.