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The field of G protein-coupled receptors has recently seen major advances in high-resolution structure determination, as well as the validation of novel paradigms of drug action, such as allosteric modulation and biased agonism, as likely universal mechanisms. These studies are opening new insights into the diversity of this receptor superfamily, teaching us new lessons in receptor functionality and hinting at novel avenues to investigate. At the same time, we are seeing exciting discoveries in GPCR intracellular signaling and physiology. The timing is right to bring together researchers in these different areas. This Keystone Symposia meeting will focus on the interplay between these discoveries and how they are being used to advance GPCR-based research toward improved clinical outcomes.