G protein-coupled receptors (GPCRs) are the major class of sensory proteins and a primary therapeutic target in the pathways to pain and itch. GPCRs are complex signaling machines. Their association with ligands, other receptors, and signaling and regulatory partners induces GPCRs to adopt distinct conformations and to traffic to microdomains within plasma and endosomal membranes. This conformational and positional dynamism controls GPCR signaling in time and space and defines the outcome of receptor activation. An understanding of the dynamic nature of GPCRs within primary sensory neurons and neighboring cells brings new insights into their contributions to the physiology and pathophysiology of pain and itch and provides novel opportunities for therapeutic intervention.