Robert J. Lefkowitz, MD James B. Duke Professor of Medicine Investigator, Howard Hughes Medical Institute Duke University Medical Center Seven transmembrane receptors (7TMRs), also known as G protein coupled receptors (GPCRs) represent by far the largest, most versatile, and most ubiquitous of the several families of plasma membrane receptors. They regulate virtually all known physiological processes in humans. As recently as 40 years ago, the very existence of cellular receptors for drugs and hormones was highly controversial, and there was essentially no direct means of studying these putative molecules. Today, the family of GPCRs is known to number approximately 1,000, and crystal structures have recently been solved of approximately 25 members of the family and even of a receptor-G protein complex. In my lecture, I will briefly review how the field has evolved over the past 40 years, hanging some of the story on my own research throughout this period. Then I will discuss recent developments in the field, which are changing our concepts of how the receptors function and are regulated in fundamental ways. These include the duality of signaling through G-proteins and β-arrestins; the development of “biased ligands”; and the possibility of leveraging this new mechanistic and molecular information to develop new classes of therapeutic agents. Finally, I will discuss recent biophysical and structural studies of receptor-barrestin interactions.