G-protein-coupled receptors (GPCRs) are the most numerous and variable class of membrane proteins that mediate signaling between cells and their environment. They are embedded in the cell’s membrane and serve as a bridge between external stimuli and internal responses. Thus, they regulate many biological processes, including vision, smell, neural transmission, blood pressure regulation, and immune response. The general structure of GPCRs includes 7 transmembrane alpha helices; a transmembrane N-terminal region that usually recognizes the ligand; and a transmembrane C-terminal region that interacts with the heterotrimeric G protein and other signaling partners. Although there is some variability in the ligands recognized by these receptors (from light or ions to small peptides or large proteins), each GPCR has its own unique specificity toward its ligand(s). When a ligand binds to a GPCR, it induces a conformational change in the receptor that facilitates the exchange of GDP for GTP on the Gα subunit of the associated G protein. The exchange of GDP for GTP leads to the dissociation of Gα from Gβγ. These activated Gα and Gβγ then interact with a variety of effector molecules, including adenylate cyclase, phospholipase C, and potassium channels, among others. This interaction results in the initiation of a cascade of signaling events. In addition to classical G-protein-mediated pathways, GPCRs can also activate β-arrestin, which will not only desensitize the receptor but also activate an alternate pathway. Therefore, GPCRs are capable of initiating multiple types of signaling cascades. Recent advances in structural biology (cryo-electron microscopy and X-ray crystallography) have greatly enhanced our understanding of the dynamic conformation of GPCRs during activation and have allowed for the development of rational drug design strategies for inhibiting specific receptor states. Because of their central role in normal physiological processes and disease, GPCRs represent about one-third of the current number of drugs being developed to treat various diseases and conditions, including neurological disorders, metabolic diseases, cardiovascular diseases, and cancers. Therefore, a detailed understanding of how the structural-functional properties of GPCRs relate to their overall function is essential for both basic science research and for translational medicine. This introduction provides a brief overview of the structural–functional properties of GPCRs, their activation mechanisms, and their functional capabilities, with an emphasis on their potential as novel therapeutic targets in the field of modern pharmacology.